Bone is a highly organized structure consisting of a protein matrix, primarily type 1 collagen, with hydroxyapatite mineral and cells from different lineages interspersed throughout. Skeletal tissue is composed of two distinct micro-skeletal structures—cortical bone (~80%) and trabecular bone (~20%)—that function as sites of muscle and tendon attachment for locomotion, as major storage sites for calcium, phosphate ions required for intergenerational transfer during procreation, and, as has more recently been established, endocrine organs secreting peptides working on other remote organs.

Bone remodeling, a process in which bone resorption is followed by bone formation in a well-defined spatiotemporal sequence, involves the coordinated activity of osteoclasts and osteoblasts, respectively, both of which differentiate from bone marrow precursors that lie in close proximity (Evans, 2007; Zaidi, 2007). Osteoclasts resorb old or damaged bone through the secretion of acid and enzymes that dissolve hydroxyapatite and digest the protein matrix, and their activity is tightly regulated by calcium and hydrogen ion concentrations that they generate locally (Arnett and Dempster, 1986; Zaidi et al., 1989). The resorptive hemivacuole then fills up with osteoblasts of the mesenchymal stem cell origin, which deposits collagen and non-collagenous proteins and that ultimately undergo mineralization through hydroxyapatite deposition. Osteoblasts that get embedded within the bone matrix become osteocytes, the skeletal equivalent of neurons, which sense and respond to mechanical stresses during terrestrial impact using their intertwined dendritic processes traversing the extensive lacunar network within bone (Iqbal and Zaidi, 2005). Osteoblasts, osteoclasts, and osteocytes communicate extensively with each other to couple bone formation and bone resorption. Over the years, it has also become increasingly clear that bone cells in the skeleton intimately interact with immune cells, adipocytes, and hematopoietic cells in the bone marrow, and they are further regulated by the central nervous system, pituitary gland, muscle, and fat.

In all, long-standing efforts to characterize the pathophysiology of aberrant loss or gain of bone in human disease have shed light on novel mechanisms and, importantly, unmasked new actionable targets. Below, we will discuss cellular crosstalk between bone cells, as well as the communication between the skeleton and other organ systems, namely, immune, nervous, neuroendocrine, and other major organs to highlight the therapeutic applications of integrative bone physiology.

Insights into the coupling of bone resorption and bone formation have come to light with the realization that transforming growth factor (TGF) β1 is a central player. TGFβ1, released from bone matrix during resorption, is the primary inducer of bone marrow-derived mesenchymal stem/stromal cell (BMSC) migration to the resorptive hemivacuole as well as their spatial localization (Iqbal et al., 2009; Tang et al., 2009). Disrupting the TGFβ1 gradient in mice with an activating Tgfb1 mutation recapitulates Camurati-Engelmann disease, characterized by disorganized stromal cell recruitment, dysplastic bones, and increased risk of fracture (Tang et al., 2009).

Parathyroid hormone (PTH) action on the skeleton represents a classical example of osteoblast-osteoclast coupling. Increased osteoclastic bone resorption from continuous PTH exposure is mediated through PTH receptor activation in osteoblasts, not osteoclasts (McSheehy and Chambers, 1986). The activated PTH/PTH receptor stimulates the secretion of receptor activator of nuclear factor kappa-Β ligand (RANKL), a member of the tumor necrosis factor alpha (TNFα) family that binds to RANK on osteoclast precursors to induce osteoclastic differentiation (Hsu et al., 1999; Huang et al., 2004; Lacey et al., 1998; Simonet et al., 1997). RANKL is also secreted by osteocytes, and the osteocyte-selective deletion of Rankl results in lower number of osteoclasts, highlighting the role of the osteocyte as a mechanosensor that coordinates site-specific osteoclast recruitment and bone resorption (Nakashima et al., 2011; Xiong et al., 2011; Xiong et al., 2015). Another key player in RANK-RANKL axis that couples osteoblastic activation with osteoclastic resorption is osteoprotegerin (OPG), again secreted by osteoblasts, which serves as a decoy receptor to RANKL and regulates RANK/RANKL binding ratio, and consequently, the rate of osteoclasts differentiation and action (Simonet et al., 1997; Figure 1).

Figure 1

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The recent identification of liver X receptors (LXRs) has provided further insight into the endogenous mechanism that determines the RANKL/OPG equilibrium within osteoblasts (Kleyer et al., 2012). The two types of LXRs, α and β, have been known to regulate cholesterol metabolism and the immune response (Zelcer and Tontonoz, 2006). However, in co-cultures of osteoblasts and osteoclasts, LXR ligand treatment decreased the RANKL/OPG ratio and interfered with osteoblast-induced osteoclastogenesis. This in vitro finding was supported by an ovariectomized rodent model in which LXR agonist administration attenuated osteoclast differentiation and rescued ovariectomy-induced bone loss (Kleyer et al., 2012). In this context, leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) also regulates osteoclast differentiation. LGR4, expressed in osteoclasts, binds RANKL and prevents the nuclear translocation of nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 (NFATc1), preventing osteoclastogenic gene expression. Moreover, activated NFATc1 induces transcription of Lgr4 in osteoclasts, negatively regulating RANK/RANKL-induced osteoclastogenesis (Luo et al., 2016; Zaidi and Iqbal, 2016; Figure 1).

Osteoblast-osteoclasts coupling is in fact bidirectional in that osteoclasts also affect osteoblast formation and function. EphrinB2, a transmembrane protein expressed by osteoclasts, interacts with its receptor, EphB4, on osteoblasts. EphirinB2-EphB4 signaling in osteoclasts suppresses osteoclastogenesis by inhibiting the c-Fos-NFATc1 signal, whereas in osteoblasts, it upregulates osteogenic genes, such as Osx and Runx2, and promotes bone formation (Zhao et al., 2006). Further, the osteoclast-secreted axon guidance molecule, SLIT3, stimulates osteoblast migration and proliferation by activating β-catenin. Osteoclast-specific Slit3-deficient mice thus demonstrate reduced bone mass, whereas osteoblast-specific Slit3 deletion results in normal bone mass (Kim et al., 2018; Figure 1).

Sphingolipids and other membrane-associated proteins also facilitate synchronous osteoblast-osteoclast coupling. Sphingosine-1-phosphate, a signaling sphingolipid, controls both osteoblastic bone formation and osteoclast precursor migration during bone remodeling. It also functions as a chemoattractant, directing osteoclast precursors to sites of stress (Ishii et al., 2009; Pederson et al., 2008). Likewise, semaphorins, a class of membrane-associated secreted proteins, either enhance or suppress bone formation. Semaphorin 3A (Sema3A)-deficient mice receiving recombinant Sema3A display a rescue of osteoblastic bone formation and osteoclastic bone resorption (Hayashi et al., 2012; Zaidi and Iqbal, 2012). Osteoclast-derived Sema4D, however, suppresses bone formation when it binds to its osteoblast receptor Plexin-B1 (Negishi-Koga et al., 2011).

In all, understanding the coupling of bone cells has prompted new treatments for bone diseases, such as osteoporosis, and continue to offer potential therapeutic targets. A monoclonal antibody against RANKL, denosumab, is currently popular for treating both osteoporosis and skeletal metastasis (McClung et al., 2006). Given that targeting LGR4 only affects mature osteoclasts and not precursor cells, there is a potential in using its extracellular domain as a means of binding excess RANKL to restrict bone resorption (Luo et al., 2016; Zaidi and Iqbal, 2016). Furthermore, enhancing EphrinB2-EphB4 or inhibiting Sema4D holds therapeutic promise to promote bone formation.

Three critical developmental pathways, namely bone morphogenetic protein (BMP), NOTCH, and WNT signaling pathways, remain active beyond morphogenesis to regulate adult bone remodeling. They interact with the master transcriptional regulators RUNX2, Osterix (OSX), activating transcription factor 4 (ATF4), and Schnurri-2. Other developmental genes that promote pluripotency, such as octamer-binding transcription factor 4 (Oct4) and sex-determining region Y-box 2, are also expressed in mesenchymal stem cells during osteogenic differentiation (Matic et al., 2016a). However, it has been proven conclusively that Oct4 has no role in bone homeostasis.

A fundamental role for members of the BMP family in skeletal development and remodeling is well documented. Osteoblasts and osteoclasts express multiple BMPs, namely (BMP-2, -4, -5, -7, and -9) and the BMP receptors (BMPRs), type I and II (Huntley et al., 2019; Wu et al., 2016). Intracellular BMP signaling is mediated by SMAD-dependent and non-SMAD-dependent pathways. BMP/BMPR binding phosphorylates the BMP-specific receptor-regulated SMADs, SMAD-1, -5, and -8 to form a heterodimeric SMAD-1/5/8 complex that translocates to the nucleus with SMAD-4. In the non-SMAD-dependent pathway, BMP/BMPR binding phosphorylates TGFβ-activated kinase (TAK1) and activates the JNK and p38 MAPK signaling pathways. Both pathways then increase the transcriptional activity of Runx2, Dlx5, and Osx (Wan and Cao, 2005; Wu et al., 2016). The BMP signaling pathway is regulated at many levels. Noggin (NOG), a glycoprotein secreted by osteoblasts, binds BMPs selectively and competitively inhibits BMP action on the cell surface. Osteoblast-specific Nog overexpression in mice shows decreased trabecular bone volume and impaired osteoblast function with increased fractures (Devlin et al., 2003). NOG levels in mice appear to increase with aging, which might contribute to age-related low bone turnover (Wu et al., 2003). Inhibitory SMAD proteins, such as SMAD-6 and -7, prevent downstream phosphorylation of the SMAD-1/5/8 complex. The BMP pathway is also regulated by the ubiquitin-proteasome system. For example, the SMAD-specific E3 ubiquitin protein ligase (Smurf)-1 downregulates BMP signaling in osteoblasts by promoting SMAD-1 degradation (Zhao et al., 2004; Zhu et al., 1999). Smurf1 also mediates TNF-induced suppression in osteoblastogenesis through its interaction with SMAD-6 and RUNX2 downregulation (Kaneki et al., 2006; Shen et al., 2006). Lastly, the ubiquitin-conjugating enzyme 9 targets SMAD-4 for degradation to suppress BMP pathway signaling (Wan and Cao, 2005).

The NOTCH receptor, a single transmembrane domain receptor protein required for somite maturation, is another critical developmental molecule that also regulates postnatal skeletal homeostasis. The binding of its ligands, JAGGED-1 and -2 and delta-like ligand 1–3, results in the cleavage of the NOTCH intracellular domain (NICD) by γ-secretases presenilin-1 and -2 (Bassett et al., 2008). The cleaved, active NICD undergoes nuclear translocation and interacts with CSL (CBF1, suppressor of hairless, lag-1) transcription factors to activate target gene expression (Luo et al., 2019). NOTCH signaling triggers proliferation and maintains a pool of osteoblast progenitors, while repressing differentiation of early osteoblasts to terminally differentiated cells (Engin et al., 2008; Hilton et al., 2008). Up- or downregulated NOTCH signaling yields distinct skeletal phenotypes depending on the stage of osteoblast lineage differentiation. Mice that overexpress Notch1 driven by an early promoter Col3.6 repress osteoblast differentiation and develop osteopenia (Zanotti et al., 2008). Similarly, patients with Hajdu-Cheney syndrome, a rare genetic disease characterized by significant bone loss and fractures, have gain-of-function NOTCH2 mutations. This condition was recapitulated in mice with a Notch2^Q2319X mutation, exhibiting osteopenia with excessive bone remodeling (Canalis et al., 2016). Conversely, when NOTCH ligand JAGGED-1 was deleted in osteoprogenitor cells, increased trabecular bone mass with increased osteoblast activity was noted (Lawal et al., 2017). Likewise, the loss of γ-secretases presenilin-1 and -2 in osteoblast progenitors yielded a high bone mass phenotype at an early age, but the mice progressively lost bone with aging (Engin et al., 2008)—together suggesting that a NOTCH-mediated regulatory loop maintains the population of osteolineage cells.

The WNT signaling pathway is integral to the developmental patterning of the dorsal somite and, being ubiquitously expressed, regulates cell growth and differentiation (Fuentealba et al., 2007). Canonical WNT signaling is initiated upon simultaneous binding of WNT ligands to the frizzled (FRZ) and low-density lipoprotein receptor-related protein (LRP) 5/6 receptors. Activation of the co-receptors leads to the inhibition of glycogen synthase kinase 3 activity and stabilization of β-catenin. The stabilized β-catenin subsequently undergoes nuclear translocation and interacts with the transcription factors T-cell factor and lymphoid enhancer factor to promote osteoblast gene expression (MacDonald et al., 2009). The β-catenin-mediated canonical pathway interacts with the BMP pathway through Axin-related protein (Axin)2, which promotes β-catenin degradation. Axin2-deficient mice display increased bone mass; this anabolic effect is dependent on BMP-2/4 and OSX (Yan et al., 2009).

Murine genome-wide association studies (GWAS) and the identification of WNT gene variants with significant skeletal phenotype, notably LRP5 mutations causing osteoporosis-pseudoglioma syndrome and SOST mutations leading to sclerosteosis and Van Buchem disease, have together established WNT signaling as a cornerstone of skeletal homeostasis (Boyden et al., 2002; Krishnan et al., 2006; Rivadeneira et al., 2009). Mechanistically, WNT/β-catenin activation in adult mice increases bone mass by enhancing stem cell renewal, pre-osteoblast proliferation, and osteoblast differentiation, while inhibiting osteoblast and osteocyte apoptosis (Baliram et al., 2011; Krishnan et al., 2006; Zhang et al., 2013). The downstream effects of WNT signaling, along with β-catenin-mediated osteoclast inhibition, have led to the recent development of an anti-osteoporosis drug with dual pro-anabolic and anti-resorptive actions. Romosozumab, a monoclonal antibody against the bone-specific WNT inhibitor sclerostin, now FDA-approved, has shown promising efficacy in reducing vertebral, non-vertebral, and hip fractures (Cosman et al., 2016; Saag et al., 2017). Dickkopf-1 (DKK1), another WNT inhibitor, contributes to myeloma-related bone disease as the production of DKK1 by myeloma cells increases the RANKL/OPG ratio (Qiang et al., 2008). An anti-DKK1 monoclonal antibody is now being studied for use as a potential therapeutic agent (Fulciniti et al., 2009).

The physical proximity of bone and bone marrow allows close interactions between bone cells and bone marrow-derived cells. Osteoclasts, derived from hematopoietic stem cells (HSCs), bear the immune receptor osteoclast-associated receptor (OSCAR) to activate receptor expressed on myeloid cells (TREM) 2, signal-regulator protein beta (SIRPβ) 1, and paired immunoglobulin-like receptor A (PIRA), establishing the physiologic relevance of the osteo-immune interface (Barrow et al., 2011; Otero et al., 2012; Pfeilschifter et al., 1989; Takayanagi, 2007). The RANK-RANKL interaction is mediated through the recruitment of TNF receptor-associated factor 6 and, at the same time, the phosphorylation of immune-receptor tyrosine-based activation motifs (ITAMs), such as DAP12 and Fc receptor subunit, resulting in NF-κB activation and cytosolic Ca²⁺ release. NFATc1 is then activated by calcineurin and amplified in cooperation with activator protein 1 (Asagiri et al., 2005). Consequently, gain-of-function mutations of calcineurin result in markedly increased NFATc1 and osteoclast differentiation, whereas its downregulation suppresses osteoclast formation (Sun et al., 2007). Calcineurin inhibitors like tacrolimus, a commonly used immunosuppressant, can cause low bone turnover and reduced bone formation (Epstein et al., 2003; Sun et al., 2005). CanA-deficient mice showed markedly reduced mineral apposition rates with osteogenic genes downregulation, namely, Runx2, Bsp, and Ocn (Sun et al., 2005). In contrast, ITAM-deficient mice (Dap12^-/-FcRγ^-/-) preserve bone mass after ovariectomy (Wu et al., 2007).

Other immune cells in the bone marrow produce several pro- and anti-osteoclastogenic cytokines that together optimize overall osteoclast differentiation. While TNFα stimulates osteoclastogenesis, IFNγ and interferon regulating factor 8 (IRF8) suppress osteoclast formation. Irf8-deficient mice thus show significant osteoporosis due to increased osteoclastogenesis (Zhao et al., 2009). Furthermore, T-helper 17 (Th17) cells secrete predominantly RANKL and TNF (compared with IFNγ), which support its contribution to hyper-resorption in autoimmune arthritis (Komatsu et al., 2014). Th17 cells secrete IL-17A, which is required for PTH to exert its catabolic effects on bone (Li et al., 2015). This is, in part, through the indirect stimulation of RANKL production by osteocytes through IL-17A signaling (Li et al., 2019). Taken together, it is clear that bone and bone marrow-derived cells interact closely to maintain skeletal homeostasis with the immune system serving as a bridge.

Findings over the past decade have established that bone remodeling and blood formation are critically entwined, with the osteoblast playing a central role in the regulation of hematopoiesis. The regulatory microenvironment, or the so-called ‘niche’ where HSCs reside, also involves BMSCs and osteoblasts (Méndez-Ferrer et al., 2010). Spindle-shaped N-cadherin+ CD45 osteoblastic cells and angiopoietin-1-expressing osteoblasts have been shown to protect and maintain HSCs in the niche (Arai et al., 2004; Zhang et al., 2003). Through WNT and NOTCH signaling, they promote HSC renewal, maturation, and survival in response to PTH (Calvi et al., 2003; Fleming et al., 2008; Weber and Calvi, 2010). Other transcriptional factors, like growth factor independence 1b, are also involved in maintaining HSC cellularity and functional integrity through the regulation of WNT signaling (Shooshtarizadeh et al., 2019). This interaction of bone marrow with bone is, in part, mediated by the sympathetic nervous system (SNS). CXCL12, a chemokine that directly causes HSC migration, is regulated by circadian secretion of noradrenaline by sympathetic nerves innervating BMSCs through β-adrenergic receptors (Katayama et al., 2006; Méndez-Ferrer et al., 2008). Thus, disrupting sympathetic signal interferes with HSC maintenance. For example, acute myelogenous leukemia-induced sympathetic neuropathy commits mesenchymal progenitors to the osteoblast lineage at the expense of HSC-maintaining periarteriolar niche cells (Hanoun et al., 2014).

In addition to regulating hematopoiesis, osteoblasts also regulate erythropoiesis by producing erythropoietin (EPO) in response to hypoxia. This increased EPO production is caused by enhanced hypoxia-inducible factor-alpha (HIF-α) signaling in osteoblastic precursors within the niche, resulting in selective expansion of the erythroid lineage (Rankin et al., 2012). Increased EPO and abnormal erythroid proliferation are proposed mechanism of low bone mass in patients with ineffective erythropoiesis such as β-thalassemia. Iron metabolism also plays a significant role in bone remodeling through action of erythroferrone (ERFE), a protein secreted by erythroblasts in bone marrow, a negative regulator of hepcidin. ERFE was shown to bind to BMP family-2, -6, and -2/6 heterodimer (Castro-Mollo et al., 2021; Wang et al., 2020). By using Erfe^-/- mice and β-thalassemic mice with systemic loss of ERFE expression (Hbb^th3/+;Erfe^-/-), our group showed that ERFE was highly expressed in osteoblasts even compared with erythroblasts, and the absence of ERFE caused high bone turnover and significant bone loss. By suppressing bone turnover from downregulating BMP-2-mediated signaling and RANKL production, ERFE was shown to exert bone protective effects (Castro-Mollo et al., 2021).

Augmented HIF-α activity enhances angiogenesis and osteogenesis (Schipani et al., 2009; Wang et al., 2007; Wu et al., 2015). Increased Hifα expression results in proliferation of a specific sub-population of endothelial cells (Type H), especially in the metaphysis of long bones, and increases the survival and proliferation of osteoprogenitors (Wang et al., 2007). The coupling of angiogenesis and osteogenesis is further highlighted by the dual role of vascular endothelial growth factor (VEGF)-A. VEGF not only promotes endothelial cell migration and proliferation, but also stimulates osteogenesis through the positive regulation of osteogenic growth factors (Schipani et al., 2009). Molecular crosstalk through angiocrine-, NOTCH-, and NOG-related signals also links angiogenesis and osteogenesis (Kusumbe et al., 2014). Defective angiocrine release of NOG, promoted by NOTCH, results in skeletal defects and impaired angiogenesis (Kusumbe et al., 2014). The effects of these signaling pathways are mediated by a subtype of vessels, called CD31^hi/Emcn^hi, which generates a distinct TGFβ3-rich microenvironment to maintain perivascular osteoprogenitors (Kusumbe et al., 2014). All of this together supports the fact that osteogenesis and angiogenesis are coupled tightly, new information that is especially critical in relation to fracture healing (Schipani et al., 2009; Wang et al., 2007).

The pituitary gland largely orchestrates peripheral hormone secretion from various endocrine organs in response to hypothalamic signals. Beyond their traditional roles, now we know that pituitary hormones also have direct effects on skeleton remodeling (Figure 2). Both osteoclasts and osteoblasts express G protein-coupled receptors (GPCRs) for thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH), growth hormone (GH), adrenocorticotropic hormone (ACTH), prolactin (PRL), oxytocin (OXT), and vasopressin (AVP) (Abe et al., 2003; Fritton et al., 2010; Seriwatanachai et al., 2008; Sun et al., 2006; Tamma et al., 2009; Tamma et al., 2013; Zaidi et al., 2010).

Figure 2

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It is challenging to examine an independent skeletal effect of pituitary hormones due to reciprocal relationship between the pituitary and the endocrine targets. Abe et al. first described an independent effect of TSH signaling using haploinsufficient TSH receptor mice (Tshr^+/-) that had normally developed thyroid follicles and normal thyroid function (Abe et al., 2003). Furthermore, induction of an iatrogenic hyperthyroid state in mice supplementing T4 caused profoundly higher bone loss in mice without the TSHR compared with wild type mice (Baliram et al., 2012). This preclinical data is consistent with strong negative correlations between low serum TSH levels and bone turnover markers, bone mineral density and fracture risk from several population-based observational studies (Aubert et al., 2017; Kim et al., 2006; Kim et al., 2021; Morris, 2007).

The skeletal effect of TSH, at least in part, is mediated through bone-active cytokines. TNFα was upregulated In Tshr^-/- mice, with RANK-L and M-CSF being unchanged (Abe et al., 2003). Compound mutants of TSHR and TNFα deficiency confirmed that TNFα plays a critical role in bone loss and increased osteoclastogenesis in the absence of TSH signaling (Hase et al., 2006; Sun et al., 2013). This is another fascinating example of interaction between endocrine and immune cells on skeletal remodeling (see above). However, the effect of TSH on osteoblasts seems not as straightforward. Our initial description of an anti-osteoblastic effect of TSH in vitro through the downregulation of VEGF receptor (FLK-1) and the WNT co-receptor, LRP5 (Abe et al., 2003), was followed by our intervention study using recombinant human TSH (rhTSH)—this showed clear evidence of an anabolic action in vivo. Intermittent administration of small dose of rhTSH increased osteoblastogenesis and bone mass, without altering thyroid hormones (Sampath et al., 2007; Sun et al., 2008). A direct anabolic effect of rhTSH in terms of inducing an elevation in the bone formation marker procollagen 1 intact N-terminal pro-peptide was also established in people (Martini et al., 2008). Furthermore, subjects with the gain-of-function polymorphism (TSHR^D727E) displayed higher bone mass (Heemstra et al., 2008; van der Deure et al., 2008). Recent findings suggest that TSH-induced osteoblastic action might be mediated by β-arrestin, which serves as a scaffold linking GPCRs to Erk1/2 signaling. TSH-induced binding of β-arrestin-1 to TSHR, which then phosphorylated Akt1, p38, and Erk1/2 and, by doing so, upregulated Alp, Rankl, and Opn. Knockdown of β-arrestin-1 inhibited TSHR-mediated osteogenic gene upregulation (Boutin et al., 2020; Cassier et al., 2017; Ramajayam et al., 2012). In all, these studies are meaningful clinically, in that they could explain the bone loss in patients with subclinical hyperthyroidism, where TSH levels are low and serum thyroid hormones are relatively normal. With that said, it also seems clear that it may be unnecessary to over-suppress serum TSH in patients other than in patients with thyroid cancer, where such suppression is clinically necessary. In that situation, an anti-resorptive therapy may be mandated to prevent bone loss.

In 2006, we reported for the first time that FSH also directly regulates bone remodeling. It acts on FSH receptors (FSHRs) coupled to the G protein, G_i2α, to increase osteoclastic bone resorption and suppress bone formation (Robinson et al., 2010; Sun et al., 2006; Sun et al., 2007; Zhu et al., 2012b). FSH also enhances RANK and, by doing so, indirectly promotes osteoclastogenesis by stimulating the release or altering the receptor expression of TNFα, IL-1β, and IL-6 (Cannon et al., 2010; Cannon et al., 2011; Iqbal et al., 2006; Wang et al., 2015).

Haploinsufficient FSHR mice (Fshr^+/-) had normal estrogen levels and developed an intact uterus; yet they showed higher bone mass compared with wild type mice (Sun et al., 2006). A separate study also showed higher bone volume and less trabecular spacing in the absence of Fshβ (Morgan et al., 2022). In addition, administering recombinant FSHβ augmented ovariectomy-induced bone loss, while blocking with anti-FSHβ antibody reversed the ovariectomized bone loss (Liu et al., 2010; Zhu et al., 2012b). These findings are underscored by findings from human observational studies using large epidemiologic cohorts of different ethnicity, namely the Study of Women’s Health Across the Nation (SWAN), AGES-Reykjavik Study of Older Adults and Chinese cohorts, all of which noted a strong inverse correlation between serum FSH levels and bone mass independently of estrogen levels (Adami et al., 2008; Cheung et al., 2011; Gallagher et al., 2010; Randolph et al., 2003; Sowers et al., 2003; Veldhuis-Vlug et al., 2021; Wu et al., 2010; Xu et al., 2009). Moreover, women with an activating FSHR polymorphism (rs6166) display a lower bone mass and high resorption markers (Rendina et al., 2010).

Taken together, it is plausible that elevated FSH levels, which precede estrogen deficiency during the menopausal transition, contribute to the rapid bone loss that begins during the late perimenopause. Noting the therapeutic relevance of these findings in relation to results from SWAN, we developed a humanized, epitope-specific FSH-blocking antibody as a potential therapeutic for osteoporosis (Gera et al., 2020). Interestingly, we also showed that blocking FSH reduces body fat, increases energy expenditure, and prevents neurodegeneration in mouse models. It is possible therefore that FSH blockade in the early years of the menopause may, in fact, reduce the extent of bone loss, visceral obesity, energy dysregulation, and the spikes of cognitive decline that are noted as early as the late perimenopause, when, as stated above, serum FSH levels are rising in the face of normal estrogen as a response to declining ovarian reserve.

GH is, expectedly, an important hormone as a growth signal that mediates postnatal longitudinal bone growth. It is now clear that GH not only works through IGF-1, but also acts directly on the skeleton (Bouillon, 1991). GH receptor-deficient and IGF-1-deficient mice both showed a similar ~25–30% reduction in body length compared to wild type mice with a significant further reduction in mutant mice lacking both molecules (Lupu et al., 2001). Furthermore, peripheral GH administration enhanced cartilage growth in hypophysectomized and GH-deficient rodents (Isaksson et al., 1987; Isaksson et al., 1991; Ohlsson et al., 1998) and reversed the osteopenic phenotype of estrogen-deficient and liver-derived IGF-1-deficient mice (Fritton et al., 2010)—altogether suggesting a direct local skeletal effect of GH.

The systemic and local effects of IGF-1 on the skeleton have been carefully examined using genetically modified mice. Liver-specific IGF-1-deficient mice, which displayed decreased circulating IGF-1 (by ~75%), surprisingly showed normal skeletal growth with albeit impaired cortical bone parameters (Sjögren et al., 1999; Yakar et al., 1999). However, bone-specific IGF-1-deficient mice showed significantly reduced bone size and bone mass, impaired bone formation and mineralization, despite normal levels of circulating IGF-1 (Govoni et al., 2007). This indicates a critical role for locally produced IGF in skeletal regulation. A certain level of systemic IGF-1 is still required for skeletal growth. Systemic IGF-1 deletion caused greater bone loss compared with bone-specific IGF-1 deletion, and the re-expression of liver-specific IGF1 in global IGF-1-deficient mice achieved ~30% of postnatal growth (Stratikopoulos et al., 2008). In addition, a further decrement of IGF-1 below ~10% in liver-specific IGF-1-deficient mice by deleting IGF-binding protein-3 and the acid labile subunit resulted in marked growth retardation (Ohlsson et al., 2009; Yakar et al., 2009). Together, these findings suggest that GH, systemic IGF-1, and local IGF-1 exert a direct effect on postnatal skeletal growth.

We found that ACTH was also directly involved in bone remodeling by bypassing known glucocorticoid-mediated action. ACTH enhances osteoblastic differentiation by upregulating the protease inhibitor alpha-2-macroglobulin, which likely promotes osteoblastic differentiation through TGFβ induction (Sadeghi et al., 2020). It also increases VEGF expression through the melanocortin receptor MC2R on osteoblasts (Zaidi et al., 2010). Given the pathophysiologic role of vascular insufficiency due to VEGF suppression in avascular necrosis (AVN) of the femur, ACTH can be a therapeutic target for treating AVN of the femur (Kerachian et al., 2010; Sadeghi et al., 2020).

Other pituitary hormones like PRL and OXT are also implicated in calcium homeostasis and bone remodeling. Pregnancy and lactation are characterized by excessive maternal bone resorption and bone loss, both of which are reversed upon weaning (Sowers et al., 1995; Wysolmerski, 2002). PRL inhibits bone formation and stimulates bone resorption by suppressing OPG (Coss et al., 2000; Seriwatanachai et al., 2008). During pregnancy, OXT appears to facilitate maternal skeletal mobilization for fetal bone ossification through increased osteoclastic resorption and suppressed bone formation (Liu et al., 2009). Genetically modified Oxt- and Oxtr-deficient mice displayed severe age-related bone loss due mainly to a bone-forming defect (Tamma et al., 2009). Consistent with this, osteoblast- and osteoclast-specific deletion of Oxtrs showed low and high bone mass, respectively (Sun et al., 2019).

Vasopressin, a key regulator of serum osmolality and fluid status, has also been implicated in bone remodeling. In contrast to Oxtr-deficient mice, Avpr-null mice displayed a high bone mass phenotype arising from increased bone formation and reduced bone resorption, indicating that vasopressin negatively regulates skeletal remodeling (Sun et al., 2016; Tamma et al., 2013). This finding might explain the profound bone loss in patients with chronic hyponatremia, which is often accompanied by high vasopressin levels (Tamma et al., 2013).

Lastly, and importantly, there is emerging evidence that certain pituitary hormones are produced locally by bone marrow-derived cells and regulate bone remodeling in a paracrine manner. ACTH is produced by macrophages (Pállinger and Csaba, 2008), suggesting that MC2R in bone may be regulated locally in addition to its systemic control. Macrophage and CD11β⁺ cells also express a splice variant of TSH, TSHβv, which is biologically active and confers an osteoprotective effect (Baliram et al., 2013; Baliram et al., 2016). In all, therefore, new pituitary-bone circuitry of biologic and medical importance continues to evolve through the use of genetically mouse models. This provides the framework for the extension of such circuitry in the regulation of other somatic and central functions, such as body fat regulation, energy metabolism, inflammation, and central neural functions, by pituitary hormones—a new physiology that is just beginning to be unearthed.

A brain-bone connection has been evident from multiple human and mouse studies. Early studies established the SNS as a negative regulator of bone formation through the action of the adipokine, leptin, and the hypothalamic leptin receptor (LEPR) (Yamashita et al., 1998; Figure 2). Intracerebroventricular leptin administration reduced bone mass and bone formation (Ducy et al., 2000), actions that were mediated by osteoblastic β2-adrenergic receptors (Adrb2) (Takeda et al., 2002). The therapeutic potential of non-selective β-adrenergic antagonists, like propranolol, in bone mass regulation in people has also been confirmed (Reid et al., 2005; Schlienger et al., 2004; Takeda et al., 2002). In contrast, the osteoclastic effect of leptin is facilitated by two distinct, antagonistic pathways. Leptin-mediated SNS activation promotes osteoclastogenesis through increased RANKL expression, which is counteracted by increased secretion of the neuropeptide CART by the hypothalamus secondary to leptin-LEPR binding (Elefteriou et al., 2005).

At the level of sympathetic ganglia, leptin-enhanced sympathetic outflow is initiated by the transcription factor FOXO1, which in turn increases the expression of dopamine β-hydroxylase (Kajimura et al., 2014). The upregulation of molecular clock genes, namely Per and Cry, downstream of Adrb2 activation promotes osteoblast proliferation through upregulation of c-fos and Jun (Fu et al., 2005). These findings suggest that the process of bone remodeling relies on oscillations of gene expression or circadian rhythmicity (Fu et al., 2005). Of note, parasympathetic nerve terminals originating from the spinal cord release acetylcholine (ACh) to interact with nicotinic ACh receptors and antagonize SNS tone, thus inhibiting bone resorption and increasing bone mass (Bajayo et al., 2012). Central parasympathetic regulation is mediated by IL-1 (Bajayo et al., 2012; Bajayo et al., 2005).

In addition to SNS and parasympathetic regulation, multiple other neuronal signaling cascades have been implicated in the complex neuronal-bone interaction, namely, melanocortin-4 receptor, Y-receptor, cannabinoid receptor, and neuromedin U (Bajayo et al., 2005; Baldock et al., 2002; Karsak et al., 2005; Ofek et al., 2006; Sato et al., 2007; Shi and Baldock, 2012). The peripheral cannabinoid receptor (CB2) that regulates appetite and energy balance also regulates bone turnover by modulating sympathetic innervation. Mice with a targeted deletion of Cb2 gene show markedly accelerated age-related trabecular bone loss and cortical expansion with high bone turnover (Ofek et al., 2006) In addition, GWAS showed an association of a single polymorphism and haplotype encompassing CB2 gene on human chromosome 1p36 (Karsak et al., 2005). On the other hand, the central cannabinoid receptor type 1 (CB1), which is present in sympathetic terminals, interacts with endocannabinoid 2-arachidonoylglycerol to suppress norepinephrine release and prevent Adrb2 activation in bone, resulting in increased bone mass (Tam et al., 2008). Further, upregulating the NO-cGMP-PKG signaling by inhibiting phosphodiesterase (PDE)-5A, which expressed in sympathetic neurons of the locus coeruleus, raphe pallidus, and paraventricular nucleus of the hypothalamus, suppresses bone remodeling (Kim et al., 2020b). In addition, recent studies show that sympathetic nerves that richly innervate the vestibular cells of the inner ear also regulate bone remodeling peripherally. In fact, bilateral vestibular lesions in mice caused peripheral bone loss due to decreased bone formation and increased resorption (Vignaux et al., 2015). This finding may be relevant to the osteoblast dysfunction in elderly patients with osteoporosis, many of whom also have vestibular dysfunction.

Given the extensive central regulation of skeletal homeostasis, it comes as no surprise that the bone can also signal back to the brain to modulate this regulation. Recent findings indicate that bone-derived signals can affect cognitive function and fetal brain development. GPCRs for osteocalcin, namely Gpr158, have been identified in brain (Khrimian et al., 2017; Obri et al., 2018), and uncarboxylated osteocalcin (GluOCN) has been shown to cross the blood-brain barrier to accumulate in specific regions of the brain, primarily the midbrain and brainstem (Oury et al., 2013). Furthermore, osteocalcin-deficient mice demonstrated a behavioral phenotype of passivity (Ducy et al., 1996; Obri et al., 2018) independently of abnormal glucose homeostasis (Pi et al., 2008). In addition to behavioral changes, osteocalcin-deficient mice of both sexes also displayed major deficits in learning and memory (Oury et al., 2013). Further anatomic examination revealed smaller brain sizes—the dentate gyrus of the hippocampus was 30% smaller and the corpus callosum was often missing, both of which are consistent with decreased spatial learning and memory (Oury et al., 2013). At a biochemical level, the midbrain and brainstem of osteocalcin-deficient mice had significantly lower amounts of monoamine neurotransmitters, including dopamine, serotonin, and norepinephrine. There was also significantly higher accumulation of the inhibitory neurotransmitter GABA in the same regions (Oury et al., 2013). These finding are supported by intracerebroventricular infusions of osteocalcin in Ocn^-/- mice that rescued the anxiety and depression phenotypes (Oury et al., 2013). Furthermore, injections of plasma from wild type mice and osmotic pumps delivering osteocalcin rescued defects in cognition and anxiety (Khrimian et al., 2017). Taken together, these findings show that osteocalcin regulates neurotransmitter synthesis and affect behavior.

Situated close to each other, bone and muscle work as a functional unit, clinically demonstrated by the fact that osteoporosis occurs with sarcopenia (Edwards et al., 2015). Spinal cord injury, which is associated with severe osteoporosis and progressive muscle loss, is a striking example of the functional interdependence of muscle and bone (Bauman et al., 1999). Spinal cord injury-induced bone resorption and bone loss are normalized after electrical stimulation of denervated muscle in rats (Qin et al., 2013), which suggests a non-neural, molecular connection between bone and muscle.

Skeletal muscle is indeed a recognized endocrine organ, secreting numerous cytokines and growth factors, collectively termed myokines (Gomarasca et al., 2020). Irisin, released upon exercise, is a suspected candidate for a non-neural, bone-muscle link. Irisin administered to rodents increased bone mass by enhancing ERK signaling and upregulating expression of the osteoblastogenic genes Atf4, Runx2, Osx, Lrp5, and β-catenin (Colaianni et al., 2014; Colaianni et al., 2015; Zhang et al., 2017). Surprisingly, irisin did not only increase bone formation by inhibiting sclerostin expression, but also suppressed RANKL-induced osteoclastogenesis (Zhang et al., 2017). In contrast, myostatin, a member of the TGFβ superfamily, regulates osteogenesis negatively. Myostatin deficiency results in an overall increase in bone density, strength, and mineralization (Carnac et al., 2007; Eijken et al., 2007; Elkasrawy and Hamrick, 2010; McPherron et al., 1997). Myostatin is overexpressed in bone of diabetic Lepr^db−/− mice with a tibial defect. Inhibiting myostatin by direct injection of its antagonist, follistatin into the site of the defect, resulted in improved bone regeneration, osteoblast proliferation and differentiation, and calcification. Taken together, these findings indicate that follistatin exerts a pro-osteogenic effect secondary to myostatin blockade (Amthor et al., 2004; Cash et al., 2009; Wallner et al., 2017). The negative skeletal remodeling induced by myostatin appears to be the result of suppressed WNT signaling. In murine osteocytes, myostatin-induced epigenetic changes through osteocyte-derived microRNA-218 (miR-218) and other exosomes has been shown to increase sclerostin and DKK1 expression, resulting ultimately in suppressed osteoblastogenesis (Li et al., 2016; Qin et al., 2017).

The deletion of bone-specific, muscle-specific, or commonly expressed genes in both bone and muscle cells also provide further insights into the muscle-bone connection. The osteocyte-specific deletion of the MBTPS1 protease increased muscle regeneration by upregulation of Pax7, Myog, Myod1, Notch, and Myh3 expression resulting in increased muscle mass and contractility (Gorski et al., 2016). Further, skeletal muscle-specific deletion of the Baml1 gene, which encodes a molecular clock transcription factor, impaired muscle function, but caused bone and cartilage defects (Schroder et al., 2015). Likewise, osteocalcin, which is primarily secreted from bone cells, promotes nutrient uptake in myofibers with exercise (Mera et al., 2016a; Mera et al., 2016b). The downregulation of methyltransferase 21C, which methylate chaperones in bone and muscle, reduces myogenesis as well as osteocyte survival (Huang et al., 2014). Similarly, ryanodine receptors integrate cytosolic Ca²⁺ signals in both osteoclasts and muscle cells (Zaidi et al., 1989; Zaidi et al., 1992; Zaidi et al., 1995).

Bone and adipose tissue remodeling occur through a complex neuroendocrine circuit that involves the brain, pituitary gland, adipose depots, and the skeleton. As noted above, a non-classical action of FSH was implicated not only in bone remodeling (see above), but also in promoting adipogenicity. The perimenopausal transition, which is accompanied by the early rise of FSH followed by estrogen deficiency, is associated with increased visceral obesity and dysregulated energy homeostasis. Our group has shown that inhibiting FSH signaling both genetically in Fshr^+/- mice and pharmacologically using an FSH-blocking antibodies in mice dramatically reduces fat in all depots, including bone marrow, and induces thermogenic beige adipose tissue (Gera et al., 2020; Zhu et al., 2012a). This action is exerted through high-affinity FSHRs present on both white and brown adipocytes (Liu et al., 2017).

The interaction of the skeleton with the brain and fat is, in part, mediated by adipokines and the SNS. Leptin- and leptin receptor-deficient mice are phenotypically obese and hypogonadal (Ducy et al., 2000). Adiponectin partially counteracts leptin’s action by decreasing sympathetic tone, which is opposed by its peripheral effect by suppressing osteoblastogenesis directly (Kajimura et al., 2013). Also worth noting is that fatty acids secreted by adipocytes, such as palmitate, exert a lipotoxic effect on osteoblasts and osteocytes and their precursors in the bone marrow (Al Saedi et al., 2019; Gunaratnam et al., 2014). ‘Hunger hormones’ such as peptide Y and ghrelin have also been linked to bone loss in patients after gastric bypass due to a paradoxical increase in bone marrow fat (Kim et al., 2020a).

The role of osteocalcin in glucose homeostasis is also noteworthy. GluOCN binds to the GPR6A to stimulate pancreatic β-cell proliferation and insulin secretion; in turn, insulin favors GluOCN bioactivity (Ferron et al., 2008; Fulzele et al., 2010; Pi et al., 2011; Wei et al., 2014b). Osteoblast-specific insulin receptor-deficient mice showed low levels of GluOCN with reduced bone formation. These mice developed obesity and insulin resistance with aging, which was improved by GluOCN administration (Fulzele et al., 2010). Additionally, delta like-1 (DLK) protein, which is expressed by the pancreas in response to GluOCN and counteracts the stimulatory effect of insulin on osteoblast proliferation (Abdallah et al., 2015). Likewise, leptin-induced SNS activation results in the upregulation of osteotesticular phosphatase, which inhibits osteocalcin activity (Hinoi et al., 2008). Finally, osteocalcin not only works as an insulin secretagogue, but also improves insulin sensitivity. Daily administration of GluOCN in mice increased mitochondrial activity in skeletal tissue, associated with increased energy expenditure (Ferron et al., 2012). Obese mice with insulin resistance after high-fat diet displayed decreased GluOCN levels (Wei et al., 2014a). Observational data in humans is, however, somewhat conflicting due to confounding factors and heterogenous study designs. In type 1 diabetes patients, GluOCN was positively associated with the C-peptide/glucose ratio (Thrailkill et al., 2012); however, osteoporotic patients receiving bisphosphonates, known to suppress bone turnover, did not show a correlation between GluOCN levels and glucose homeostasis parameters, such as fasting glucose or insulin levels (Hong et al., 2013).

Lastly, interest in bone marrow fat has gained significant traction in recent years as aging in both sexes and menopause in women are associated with profound increases in bone marrow fat deposition (Suchacki et al., 2016). Bone marrow adipocytes, interestingly, display a signature of osteogenic precursor markers, such as Osx, Runx2, and Lepr, suggesting a mesenchymal origin, as with osteoblasts (Matic et al., 2016b). Some consider BMSC differentiation into a bone marrow adipocyte as the default, unless it is committed to the osteoblast lineage (Pierce et al., 2019). The expression of PPARγ, CCAAT/enhancer-binding protein α, and secreted frizzled related protein 1 promote BMSC commitment to bone marrow adipocyte differentiation, whereas IGF-1 and adiponectin inhibit adipocyte differentiation (Tencerova and Kassem, 2016). Thus, patients receiving thiazolidinedione develop osteopenia as PPARγ activation stimulates adipogenesis at the expense of osteoblastogenesis (Cawthorn et al., 2014; Lu et al., 2016; Tsuchida et al., 2005). And LepR signaling in BMSC promotes adipogenesis and inhibits osteoblastogenesis in response to diet (Yue et al., 2016). The zinc finger nuclease, ZFP467, also plays a role in determining BMSC fate (Quach et al., 2011). ZFP467-deficient mice demonstrate increased trabecular bone volume and a significant reduction in marrow adipose tissue (Le et al., 2021). The osteoanabolic and anti-adipogenic effects of PTH are, in part, mediated by suppressing Zfp467 expression (Fan et al., 2017; Le et al., 2021). A recent study has shown that a subpopulation of BMSCs, called marrow adipogenic lineage precursors, express RANKL and regulate osteoclastic bone resorption (Yu et al., 2021).

Vital organs function in coordination to maintain bodily homeostasis, and this crosstalk between organs is achieved through complex biological communications and feedback mediated through cellular, soluble, and neurohormonal pathways (Armutcu, 2019). For example, fibroblast growth factor (FGF) 23 from osteocytes binds to the FGF receptor 1-Klotho complex in the kidney to promote phosphate excretion (Nakatani et al., 2009; Shimada et al., 2004; Shimada et al., 2001). Clinical observation of decreased bone mass in patients with pathologies of other vital organs has provided additional insight into the integrative nature of skeletal physiology. For example, osteoporosis and osteopenia are prevalent with chronic liver diseases, especially with cholestatic liver disease (Ninkovic et al., 2002). In vitro studies have shown that treatment with unconjugated bilirubin or serum from jaundiced patients significantly reduced viability and differentiation of osteoblast-like cells and primary osteoblasts (Janes et al., 1995; Ruiz-Gaspà et al., 2011), with a significantly increased RANKL/OPG ratio (Ruiz-Gaspà et al., 2011). Taurine, which is primarily synthesized in liver, mediates GH-dependent IGF-1 synthesis and subsequently enhances osteoblast function (Clemens, 2014). Since vitamin B₁₂ is required for taurine synthesis, the deletion of gastric intrinsic factor causes low bone mass in mice, which is subsequently rescued by taurine supplementation (Clemens, 2014; Roman-Garcia et al., 2014). Likewise, patients with chronic obstructive pulmonary disease, even when clinically stable, often demonstrate increased inflammatory markers and lower BMD (Liang and Feng, 2012). The association of heart disease and osteoporosis is also worth noting. Secondary hyperparathyroidism can occur in patients with heart failure independent of renal function (Altay et al., 2012). Moreover, upregulation of the renin-angiotensin-aldosterone (RAA) axis in heart failure might promote RANKL expression and osteoclast differentiation (Guan et al., 2011). In all, the skeleton is directly and indirectly intertwined with other vital organs, and new advances in integrative physiology continue to expand the breadth of our understanding of skeletal physiology.

Aging-related dysfunction in non-skeletal organ can affect skeletal homeostasis. Decreased organ function and chronic inflammation with aging, which cause changes in hemodynamics, RAA system, and SNS, can disturb bone remodeling (Oishi and Manabe, 2020). The Wnt-related proteins were shown to be downregulated in osteoblasts with aging (Rauner et al., 2008), which was partly mediated by increased endogenous glucocorticoids and oxidized lipid-induced PPARγ activation (Manolagas, 2010). In addition, aging-associated changes in HSCs may cause aggressive osteoclastic bone resorption (Møller et al., 2020).

Sex undoubtedly has a major impact on organ crosstalk. Many factors, including sex-specific genes, genetic imprinting, and sex steroids, are involved in the regulation of key signaling pathways. For example, the difference in the relative levels of calcification and fibrosis in heart valves in male and female may be attributed to differences in BMP/TGFβ signaling (Shah and Rogers, 2018). Notably, estrogen directly induces Bmp2 and Bmp6 transcription (Zhou et al., 2003) and stimulates SMAD-2/3 protein degradation (Ito et al., 2010).

Understanding the integrative nature of skeletal physiology has opened up the potential for new therapeutic targets for osteoporosis. Osteo-induction by BMPs has long been utilized to accelerate fracture healing, with recombinant human BMP-2 use approved in bone grafts for treating acute, open tibial shaft fractures (Salazar et al., 2016). Our group recently developed a fully humanized, multipurpose blocking antibody specific to FSHβ targeting both postmenopausal osteoporosis and the accompanying visceral obesity and neurodegeneration (Gera et al., 2020). Upregulating LXR activity has been explored as it suppresses osteoclastogenesis and confers cardioprotection, making LXR agonists a potential dual treatment for osteoporosis and cardiovascular disease (Kleyer et al., 2012; Ma et al., 2017). Osteocalcin, given that it regulates bone remodeling, glucose, and energy homeostasis, and seems to be involved in age-related cognitive decline, is a promising multisystem therapeutic target (Obri et al., 2018).

Due to the common signaling pathways involved in the homeostasis of bone and other organ systems, using existing pharmacotherapies in different applications is also possible. For example, our group showed that nitrogen-containing bisphosphonates can directly inhibit the growth of EGFR-driven cancer cells, making it possible to potentially repurpose them to treat lung, breast, gastrointestinal, head and neck, and other cancers (Stachnik et al., 2014; Yuen et al., 2014). PDE5 inhibitors, a class of commonly used drugs for treating erectile dysfunction and pulmonary hypertension, have shown a combined anabolic and anti-resorptive action in the skeleton (Kim et al., 2020b), highlighting the possibility of targeting the NO-cGMP-PKG pathway in treating osteoporosis (Kim et al., 2020c). Similarly, meclizine, an anti-histamine used for treating vertigo and motion sickness, is being tested for its ability to enhance growth in achondroplasia by inhibiting FGF receptor 3, a negative regulator of endochondral bone growth (Matsushita et al., 2015). Lastly, statins, which block HMG-CoA reductase, promote bone formation in rats (; Zhu et al., 2021). Conversely, the lack of HMG-CoA reductase decreases osteoclast survival, indicating the possibility of repurposing statins for treating bone loss (Luegmayr et al., 2004).

In sum, recent interest in skeletal physiology in the context of intercellular and interorgan communication affords a myriad of translational and clinical possibilities. The complex crosstalk links seemingly divergent processes and systems increasingly intimately, with new therapeutic targets being identified at a rapid rate. As implied above, these discoveries are paving the way for a new clinical paradigm, one that entails using single agent to treat multiple, co-existing diseases.

1. 1. Abdallah BM
   2. Ditzel N
   3. Laborda J
   4. Karsenty G
   5. Kassem M

   (2015) DLK1 regulates whole-body glucose metabolism: A negative feedback regulation of the osteocalcin-insulin loop

   Diabetes 64:3069–3080.

   https://doi.org/10.2337/db14-1642

   • PubMed
   • Google Scholar
2. 1. Abe E
   2. Marians RC
   3. Yu W
   4. Wu X-B
   5. Ando T
   6. Li Y
   7. Iqbal J
   8. Eldeiry L
   9. Rajendren G
   10. Blair HC
   11. Davies TF
   12. Zaidi M

   (2003) Tsh is a negative regulator of skeletal remodeling

   Cell 115:151–162.

   https://doi.org/10.1016/S0092-8674(03)00771-2

   • PubMed
   • Google Scholar
3. 1. Adami S
   2. Bianchi G
   3. Brandi ML
   4. Giannini S
   5. Ortolani S
   6. DiMunno O
   7. Frediani B
   8. Rossini M
   9. BONTURNO study group

   (2008) Determinants of bone turnover markers in healthy premenopausal women

   Calcified Tissue International 82:341–347.

   https://doi.org/10.1007/s00223-008-9126-5

   • PubMed
   • Google Scholar
4. 1. Al Saedi A
   2. Bermeo S
   3. Plotkin L
   4. Myers DE
   5. Duque G

   (2019) Mechanisms of palmitate-induced lipotoxicity in osteocytes

   Bone 127:353–359.

   https://doi.org/10.1016/j.bone.2019.06.016

   • PubMed
   • Google Scholar
5. 1. Altay H
   2. Zorlu A
   3. Binici S
   4. Bilgi M
   5. Yilmaz MB
   6. Colkesen Y
   7. Erol T
   8. Muderrisoglu H

   (2012) Relation of serum parathyroid hormone level to severity of heart failure

   The American Journal of Cardiology 109:252–256.

   https://doi.org/10.1016/j.amjcard.2011.08.039

   • PubMed
   • Google Scholar
6. 1. Amthor H
   2. Nicholas G
   3. McKinnell I
   4. Kemp CF
   5. Sharma M
   6. Kambadur R
   7. Patel K

   (2004) Follistatin complexes myostatin and antagonises myostatin-mediated inhibition of myogenesis

   Developmental Biology 270:19–30.

   https://doi.org/10.1016/j.ydbio.2004.01.046

   • PubMed
   • Google Scholar
7. 1. Arai F
   2. Hirao A
   3. Ohmura M
   4. Sato H
   5. Matsuoka S
   6. Takubo K
   7. Ito K
   8. Koh GY
   9. Suda T

   (2004) Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche

   Cell 118:149–161.

   https://doi.org/10.1016/j.cell.2004.07.004

   • PubMed
   • Google Scholar
8. 1. Armutcu F

   (2019) Organ crosstalk: the potent roles of inflammation and fibrotic changes in the course of organ interactions

   Inflammation Research 68:825–839.

   https://doi.org/10.1007/s00011-019-01271-7

   • PubMed
   • Google Scholar
9. 1. Arnett TR
   2. Dempster DW

   (1986) Effect of ph on bone resorption by rat osteoclasts in vitro

   Endocrinology 119:119–124.

   https://doi.org/10.1210/endo-119-1-119

   • PubMed
   • Google Scholar
10. 1. Asagiri M
    2. Sato K
    3. Usami T
    4. Ochi S
    5. Nishina H
    6. Yoshida H
    7. Morita I
    8. Wagner EF
    9. Mak TW
    10. Serfling E
    11. Takayanagi H

    (2005) Autoamplification of nfatc1 expression determines its essential role in bone homeostasis

    The Journal of Experimental Medicine 202:1261–1269.

    https://doi.org/10.1084/jem.20051150

    • PubMed
    • Google Scholar
11. 1. Aubert CE
    2. Floriani C
    3. Bauer DC
    4. da Costa BR
    5. Segna D
    6. Blum MR
    7. Collet T-H
    8. Fink HA
    9. Cappola AR
    10. Syrogiannouli L
    11. Peeters RP
    12. Åsvold BO
    13. den Elzen WPJ
    14. Luben RN
    15. Bremner AP
    16. Gogakos A
    17. Eastell R
    18. Kearney PM
    19. Hoff M
    20. Le Blanc E
    21. Ceresini G
    22. Rivadeneira F
    23. Uitterlinden AG
    24. Khaw K-T
    25. Langhammer A
    26. Stott DJ
    27. Westendorp RGJ
    28. Ferrucci L
    29. Williams GR
    30. Gussekloo J
    31. Walsh JP
    32. Aujesky D
    33. Rodondi N
    34. Thyroid Studies Collaboration

    (2017) Thyroid function tests in the reference range and fracture: individual participant analysis of prospective cohorts

    The Journal of Clinical Endocrinology and Metabolism 102:2719–2728.

    https://doi.org/10.1210/jc.2017-00294

    • PubMed
    • Google Scholar
12. 1. Bajayo A
    2. Goshen I
    3. Feldman S
    4. Csernus V
    5. Iverfeldt K
    6. Shohami E
    7. Yirmiya R
    8. Bab I

    (2005) Central IL-1 receptor signaling regulates bone growth and mass

    PNAS 102:12956–12961.

    https://doi.org/10.1073/pnas.0502562102

    • PubMed
    • Google Scholar
13. 1. Bajayo A
    2. Bar A
    3. Denes A
    4. Bachar M
    5. Kram V
    6. Attar-Namdar M
    7. Zallone A
    8. Kovács KJ
    9. Yirmiya R
    10. Bab I

    (2012) Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual

    PNAS 109:15455–15460.

    https://doi.org/10.1073/pnas.1206061109

    • PubMed
    • Google Scholar
14. 1. Baldock PA
    2. Sainsbury A
    3. Couzens M
    4. Enriquez RF
    5. Thomas GP
    6. Gardiner EM
    7. Herzog H

    (2002) Hypothalamic Y2 receptors regulate bone formation

    The Journal of Clinical Investigation 109:915–921.

    https://doi.org/10.1172/JCI14588

    • PubMed
    • Google Scholar
15. 1. Baliram R
    2. Latif R
    3. Berkowitz J
    4. Frid S
    5. Colaianni G
    6. Sun L
    7. Zaidi M
    8. Davies TF

    (2011) Thyroid-stimulating hormone induces a wnt-dependent, feed-forward loop for osteoblastogenesis in embryonic stem cell cultures

    PNAS 108:16277–16282.

    https://doi.org/10.1073/pnas.1110286108

    • PubMed
    • Google Scholar
16. 1. Baliram R
    2. Sun L
    3. Cao J
    4. Li J
    5. Latif R
    6. Huber AK
    7. Yuen T
    8. Blair HC
    9. Zaidi M
    10. Davies TF

    (2012) Hyperthyroid-associated osteoporosis is exacerbated by the loss of TSH signaling

    The Journal of Clinical Investigation 122:3737–3741.

    https://doi.org/10.1172/JCI63948

    • PubMed
    • Google Scholar
17. 1. Baliram R
    2. Chow A
    3. Huber AK
    4. Collier L
    5. Ali MR
    6. Morshed SA
    7. Latif R
    8. Teixeira A
    9. Merad M
    10. Liu L
    11. Sun L
    12. Blair HC
    13. Zaidi M
    14. Davies TF

    (2013) Thyroid and bone: macrophage-derived TSH-β splice variant increases murine osteoblastogenesis

    Endocrinology 154:4919–4926.

    https://doi.org/10.1210/en.2012-2234

    • PubMed
    • Google Scholar
18. 1. Baliram R.
    2. Latif R
    3. Morshed SA
    4. Zaidi M
    5. Davies TF

    (2016) T3 regulates a human macrophage-derived TSH-β splice variant: implications for human bone biology

    Endocrinology 157:3658–3667.

    https://doi.org/10.1210/en.2015-1974

    • PubMed
    • Google Scholar
19. 1. Barrow AD
    2. Raynal N
    3. Andersen TL
    4. Slatter DA
    5. Bihan D
    6. Pugh N
    7. Cella M
    8. Kim T
    9. Rho J
    10. Negishi-Koga T
    11. Delaisse J-M
    12. Takayanagi H
    13. Lorenzo J
    14. Colonna M
    15. Farndale RW
    16. Choi Y
    17. Trowsdale J

    (2011) Oscar is a collagen receptor that costimulates osteoclastogenesis in DAP12-deficient humans and mice

    The Journal of Clinical Investigation 121:3505–3516.

    https://doi.org/10.1172/JCI45913

    • PubMed
    • Google Scholar
20. 1. Bassett JHD
    2. Williams AJ
    3. Murphy E
    4. Boyde A
    5. Howell PGT
    6. Swinhoe R
    7. Archanco M
    8. Flamant F
    9. Samarut J
    10. Costagliola S
    11. Vassart G
    12. Weiss RE
    13. Refetoff S
    14. Williams GR

    (2008) A lack of thyroid hormones rather than excess thyrotropin causes abnormal skeletal development in hypothyroidism

    Molecular Endocrinology 22:501–512.

    https://doi.org/10.1210/me.2007-0221

    • PubMed
    • Google Scholar
21. 1. Bauman WA
    2. Spungen AM
    3. Wang J
    4. Pierson RN
    5. Schwartz E

    (1999) Continuous loss of bone during chronic immobilization: a monozygotic twin study

    Osteoporosis International 10:123–127.

    https://doi.org/10.1007/s001980050206

    • PubMed
    • Google Scholar
22. 1. Bouillon R

    (1991) Growth hormone and bone

    Hormone Research 36 Suppl 1:49–55.

    https://doi.org/10.1159/000182189

    • PubMed
    • Google Scholar
23. 1. Boutin A
    2. Gershengorn MC
    3. Neumann S

    (2020) β-arrestin 1 in thyrotropin receptor signaling in bone: studies in osteoblast-like cells

    Frontiers in Endocrinology 11:312.

    https://doi.org/10.3389/fendo.2020.00312

    • PubMed
    • Google Scholar
24. 1. Boyden LM
    2. Mao J
    3. Belsky J
    4. Mitzner L
    5. Farhi A
    6. Mitnick MA
    7. Wu D
    8. Insogna K
    9. Lifton RP

    (2002) High bone density due to a mutation in LDL-receptor-related protein 5

    The New England Journal of Medicine 346:1513–1521.

    https://doi.org/10.1056/NEJMoa013444

    • PubMed
    • Google Scholar
25. 1. Calvi LM
    2. Adams GB
    3. Weibrecht KW
    4. Weber JM
    5. Olson DP
    6. Knight MC
    7. Martin RP
    8. Schipani E
    9. Divieti P
    10. Bringhurst FR
    11. Milner LA
    12. Kronenberg HM
    13. Scadden DT

    (2003) Osteoblastic cells regulate the haematopoietic stem cell niche

    Nature 425:841–846.

    https://doi.org/10.1038/nature02040

    • PubMed
    • Google Scholar
26. 1. Canalis E
    2. Schilling L
    3. Yee SP
    4. Lee SK
    5. Zanotti S

    (2016) Hajdu cheney mouse mutants exhibit osteopenia, increased osteoclastogenesis, and bone resorption

    The Journal of Biological Chemistry 291:1538–1551.

    https://doi.org/10.1074/jbc.M115.685453

    • PubMed
    • Google Scholar
27. 1. Cannon JG
    2. Cortez-Cooper M
    3. Meaders E
    4. Stallings J
    5. Haddow S
    6. Kraj B
    7. Sloan G
    8. Mulloy A

    (2010) Follicle-stimulating hormone, interleukin-1, and bone density in adult women

    American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 298:R790–R798.

    https://doi.org/10.1152/ajpregu.00728.2009

    • PubMed
    • Google Scholar
28. 1. Cannon JG
    2. Kraj B
    3. Sloan G

    (2011) Follicle-stimulating hormone promotes RANK expression on human monocytes

    Cytokine 53:141–144.

    https://doi.org/10.1016/j.cyto.2010.11.011

    • PubMed
    • Google Scholar
29. 1. Carnac G
    2. Vernus B
    3. Bonnieu A

    (2007) Myostatin in the pathophysiology of skeletal muscle

    Current Genomics 8:415–422.

    https://doi.org/10.2174/138920207783591672

    • PubMed
    • Google Scholar
30. 1. Cash JN
    2. Rejon CA
    3. McPherron AC
    4. Bernard DJ
    5. Thompson TB

    (2009) The structure of myostatin: follistatin 288: insights into receptor utilization and heparin binding

    The EMBO Journal 28:2662–2676.

    https://doi.org/10.1038/emboj.2009.205

    • PubMed
    • Google Scholar
31. 1. Cassier E
    2. Gallay N
    3. Bourquard T
    4. Claeysen S
    5. Bockaert J
    6. Crépieux P
    7. Poupon A
    8. Reiter E
    9. Marin P
    10. Vandermoere F

    (2017) Phosphorylation of β-arrestin2 at thr³⁸³ by MEK underlies β-arrestin-dependent activation of erk1/2 by gpcrs

    eLife 6:e23777.

    https://doi.org/10.7554/eLife.23777

    • PubMed
    • Google Scholar
32. 1. Castro-Mollo M
    2. Gera S
    3. Ruiz-Martinez M
    4. Feola M
    5. Gumerova A
    6. Planoutene M
    7. Clementelli C
    8. Sangkhae V
    9. Casu C
    10. Kim S-M
    11. Ostland V
    12. Han H
    13. Nemeth E
    14. Fleming R
    15. Rivella S
    16. Lizneva D
    17. Yuen T
    18. Zaidi M
    19. Ginzburg Y

    (2021) The hepcidin regulator erythroferrone is a new member of the erythropoiesis-iron-bone circuitry

    eLife 10:e68217.

    https://doi.org/10.7554/eLife.68217

    • PubMed
    • Google Scholar
33. 1. Cawthorn WP
    2. Scheller EL
    3. Learman BS
    4. Parlee SD
    5. Simon BR
    6. Mori H
    7. Ning X
    8. Bree AJ
    9. Schell B
    10. Broome DT
    11. Soliman SS
    12. DelProposto JL
    13. Lumeng CN
    14. Mitra A
    15. Pandit SV
    16. Gallagher KA
    17. Miller JD
    18. Krishnan V
    19. Hui SK
    20. Bredella MA
    21. Fazeli PK
    22. Klibanski A
    23. Horowitz MC
    24. Rosen CJ
    25. MacDougald OA

    (2014) Bone marrow adipose tissue is an endocrine organ that contributes to increased circulating adiponectin during caloric restriction

    Cell Metabolism 20:368–375.

    https://doi.org/10.1016/j.cmet.2014.06.003

    • PubMed
    • Google Scholar
34. 1. Cheung E
    2. Tsang S
    3. Bow C
    4. Soong C
    5. Yeung S
    6. Loong C
    7. Cheung C-L
    8. Kan A
    9. Lo S
    10. Tam S
    11. Tang G
    12. Kung A

    (2011) Bone loss during menopausal transition among southern chinese women

    Maturitas 69:50–56.

    https://doi.org/10.1016/j.maturitas.2011.01.010

    • PubMed
    • Google Scholar
35. 1. Clemens TL

    (2014) Vitamin B12 deficiency and bone health

    The New England Journal of Medicine 371:963–964.

    https://doi.org/10.1056/NEJMcibr1407247

    • PubMed
    • Google Scholar
36. 1. Colaianni G
    2. Cuscito C
    3. Mongelli T
    4. Oranger A
    5. Mori G
    6. Brunetti G
    7. Colucci S
    8. Cinti S
    9. Grano M

    (2014) Irisin enhances osteoblast differentiation in vitro

    International Journal of Endocrinology 2014:902186.

    https://doi.org/10.1155/2014/902186

    • PubMed
    • Google Scholar
37. 1. Colaianni G
    2. Cuscito C
    3. Mongelli T
    4. Pignataro P
    5. Buccoliero C
    6. Liu P
    7. Lu P
    8. Sartini L
    9. Di Comite M
    10. Mori G
    11. Di Benedetto A
    12. Brunetti G
    13. Yuen T
    14. Sun L
    15. Reseland JE
    16. Colucci S
    17. New MI
    18. Zaidi M
    19. Cinti S
    20. Grano M

    (2015) The myokine irisin increases cortical bone mass

    PNAS 112:12157–12162.

    https://doi.org/10.1073/pnas.1516622112

    • PubMed
    • Google Scholar
38. 1. Cosman F
    2. Crittenden DB
    3. Adachi JD
    4. Binkley N
    5. Czerwinski E
    6. Ferrari S
    7. Hofbauer LC
    8. Lau E
    9. Lewiecki EM
    10. Miyauchi A
    11. Zerbini CAF
    12. Milmont CE
    13. Chen L
    14. Maddox J
    15. Meisner PD
    16. Libanati C
    17. Grauer A

    (2016) Romosozumab treatment in postmenopausal women with osteoporosis

    The New England Journal of Medicine 375:1532–1543.

    https://doi.org/10.1056/NEJMoa1607948

    • PubMed
    • Google Scholar
39. 1. Coss D
    2. Yang L
    3. Kuo CB
    4. Xu X
    5. Luben RA
    6. Walker AM

    (2000) Effects of prolactin on osteoblast alkaline phosphatase and bone formation in the developing rat

    American Journal of Physiology. Endocrinology and Metabolism 279:E1216–E1225.

    https://doi.org/10.1152/ajpendo.2000.279.6.E1216

    • PubMed
    • Google Scholar
40. 1. Devlin RD
    2. Du Z
    3. Pereira RC
    4. Kimble RB
    5. Economides AN
    6. Jorgetti V
    7. Canalis E

    (2003) Skeletal overexpression of noggin results in osteopenia and reduced bone formation

    Endocrinology 144:1972–1978.

    https://doi.org/10.1210/en.2002-220918

    • PubMed
    • Google Scholar
41. 1. Ducy P
    2. Desbois C
    3. Boyce B
    4. Pinero G
    5. Story B
    6. Dunstan C
    7. Smith E
    8. Bonadio J
    9. Goldstein S
    10. Gundberg C
    11. Bradley A
    12. Karsenty G

    (1996) Increased bone formation in osteocalcin-deficient mice

    Nature 382:448–452.

    https://doi.org/10.1038/382448a0

    • PubMed
    • Google Scholar
42. 1. Ducy P
    2. Amling M
    3. Takeda S
    4. Priemel M
    5. Schilling AF
    6. Beil FT
    7. Shen J
    8. Vinson C
    9. Rueger JM
    10. Karsenty G

    (2000) Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass

    Cell 100:197–207.

    https://doi.org/10.1016/s0092-8674(00)81558-5

    • PubMed
    • Google Scholar
43. 1. Edwards MH
    2. Dennison EM
    3. Aihie Sayer A
    4. Fielding R
    5. Cooper C

    (2015) Osteoporosis and sarcopenia in older age

    Bone 80:126–130.

    https://doi.org/10.1016/j.bone.2015.04.016

    • PubMed
    • Google Scholar
44. 1. Eijken M
    2. Swagemakers S
    3. Koedam M
    4. Steenbergen C
    5. Derkx P
    6. Uitterlinden AG
    7. van der Spek PJ
    8. Visser JA
    9. de Jong FH
    10. Pols HAP
    11. van Leeuwen JPTM

    (2007) The activin A-follistatin system: potent regulator of human extracellular matrix mineralization

    FASEB Journal 21:2949–2960.

    https://doi.org/10.1096/fj.07-8080com

    • PubMed
    • Google Scholar
45. 1. Elefteriou F
    2. Ahn JD
    3. Takeda S
    4. Starbuck M
    5. Yang X
    6. Liu X
    7. Kondo H
    8. Richards WG
    9. Bannon TW
    10. Noda M
    11. Clement K
    12. Vaisse C
    13. Karsenty G

    (2005) Leptin regulation of bone resorption by the sympathetic nervous system and CART

    Nature 434:514–520.

    https://doi.org/10.1038/nature03398

    • PubMed
    • Google Scholar
46. 1. Elkasrawy MN
    2. Hamrick MW

    (2010)

    Myostatin (GDF-8) as a key factor linking muscle mass and bone structure

    Journal of Musculoskeletal & Neuronal Interactions 10:56–63.

    • PubMed
    • Google Scholar
47. 1. Engin F
    2. Yao Z
    3. Yang T
    4. Zhou G
    5. Bertin T
    6. Jiang MM
    7. Chen Y
    8. Wang L
    9. Zheng H
    10. Sutton RE
    11. Boyce BF
    12. Lee B

    (2008) Dimorphic effects of Notch signaling in bone homeostasis

    Nature Medicine 14:299–305.

    https://doi.org/10.1038/nm1712

    • PubMed
    • Google Scholar
48. 1. Epstein S
    2. Inzerillo AM
    3. Caminis J
    4. Zaidi M

    (2003) Disorders associated with acute rapid and severe bone loss

    Journal of Bone and Mineral Research 18:2083–2094.

    https://doi.org/10.1359/jbmr.2003.18.12.2083

    • PubMed
    • Google Scholar
49. 1. Evans CH

    (2007) John Hunter and the origins of modern orthopaedic research

    Journal of Orthopaedic Research 25:556–560.

    https://doi.org/10.1002/jor.20386

    • PubMed
    • Google Scholar
50. 1. Fan Y
    2. Hanai J-I
    3. Le PT
    4. Bi R
    5. Maridas D
    6. DeMambro V
    7. Figueroa CA
    8. Kir S
    9. Zhou X
    10. Mannstadt M
    11. Baron R
    12. Bronson RT
    13. Horowitz MC
    14. Wu JY
    15. Bilezikian JP
    16. Dempster DW
    17. Rosen CJ
    18. Lanske B

    (2017) Parathyroid hormone directs bone marrow mesenchymal cell fate

    Cell Metabolism 25:661–672.

    https://doi.org/10.1016/j.cmet.2017.01.001

    • PubMed
    • Google Scholar
51. 1. Ferron M
    2. Hinoi E
    3. Karsenty G
    4. Ducy P

    (2008) Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice

    PNAS 105:5266–5270.

    https://doi.org/10.1073/pnas.0711119105

    • PubMed
    • Google Scholar
52. 1. Ferron M
    2. McKee MD
    3. Levine RL
    4. Ducy P
    5. Karsenty G

    (2012) Intermittent injections of osteocalcin improve glucose metabolism and prevent type 2 diabetes in mice

    Bone 50:568–575.

    https://doi.org/10.1016/j.bone.2011.04.017

    • PubMed
    • Google Scholar
53. 1. Fleming HE
    2. Janzen V
    3. Lo Celso C
    4. Guo J
    5. Leahy KM
    6. Kronenberg HM
    7. Scadden DT

    (2008) Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo

    Cell Stem Cell 2:274–283.

    https://doi.org/10.1016/j.stem.2008.01.003

    • PubMed
    • Google Scholar
54. 1. Fritton JC
    2. Emerton KB
    3. Sun H
    4. Kawashima Y
    5. Mejia W
    6. Wu Y
    7. Rosen CJ
    8. Panus D
    9. Bouxsein M
    10. Majeska RJ
    11. Schaffler MB
    12. Yakar S

    (2010) Growth hormone protects against ovariectomy-induced bone loss in states of low circulating insulin-like growth factor (IGF-1)

    Journal of Bone and Mineral Research 25:235–246.

    https://doi.org/10.1359/jbmr.090723

    • PubMed
    • Google Scholar
55. 1. Fu L
    2. Patel MS
    3. Bradley A
    4. Wagner EF
    5. Karsenty G

    (2005) The molecular clock mediates leptin-regulated bone formation

    Cell 122:803–815.

    https://doi.org/10.1016/j.cell.2005.06.028

    • PubMed
    • Google Scholar
56. 1. Fuentealba LC
    2. Eivers E
    3. Ikeda A
    4. Hurtado C
    5. Kuroda H
    6. Pera EM
    7. De Robertis EM

    (2007) Integrating patterning signals: wnt/GSK3 regulates the duration of the BMP/smad1 signal

    Cell 131:980–993.

    https://doi.org/10.1016/j.cell.2007.09.027

    • PubMed
    • Google Scholar
57. 1. Fulciniti M
    2. Tassone P
    3. Hideshima T
    4. Vallet S
    5. Nanjappa P
    6. Ettenberg SA
    7. Shen Z
    8. Patel N
    9. Tai Y-T
    10. Chauhan D
    11. Mitsiades C
    12. Prabhala R
    13. Raje N
    14. Anderson KC
    15. Stover DR
    16. Munshi NC

    (2009) Anti-DKK1 mab (BHQ880) as a potential therapeutic agent for multiple myeloma

    Blood 114:371–379.

    https://doi.org/10.1182/blood-2008-11-191577

    • PubMed
    • Google Scholar
58. 1. Fulzele K
    2. Riddle RC
    3. DiGirolamo DJ
    4. Cao X
    5. Wan C
    6. Chen D
    7. Faugere M-C
    8. Aja S
    9. Hussain MA
    10. Brüning JC
    11. Clemens TL

    (2010) Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition

    Cell 142:309–319.

    https://doi.org/10.1016/j.cell.2010.06.002

    • PubMed
    • Google Scholar
59. 1. Gallagher CM
    2. Moonga BS
    3. Kovach JS

    (2010) Cadmium, follicle-stimulating hormone, and effects on bone in women age 42–60 years, NHANES III

    Environmental Research 110:105–111.

    https://doi.org/10.1016/j.envres.2009.09.012

    • PubMed
    • Google Scholar
60. 1. Gera S
    2. Sant D
    3. Haider S
    4. Korkmaz F
    5. Kuo TC
    6. Mathew M
    7. Perez-Pena H
    8. Xie H
    9. Chen H
    10. Batista R
    11. Ma K
    12. Cheng Z
    13. Hadelia E
    14. Robinson C
    15. Macdonald A
    16. Miyashita S
    17. Williams A
    18. Jebian G
    19. Miyashita H
    20. Gumerova A
    21. Ievleva K
    22. Smith P
    23. He J
    24. Ryu V
    25. DeMambro V
    26. Quinn MA
    27. Meseck M
    28. Kim SM
    29. Kumar TR
    30. Iqbal J
    31. New MI
    32. Lizneva D
    33. Rosen CJ
    34. Hsueh AJ
    35. Yuen T
    36. Zaidi M

    (2020) First-in-class humanized FSH blocking antibody targets bone and fat

    PNAS 117:28971–28979.

    https://doi.org/10.1073/pnas.2014588117

    • PubMed
    • Google Scholar
61. 1. Gomarasca M
    2. Banfi G
    3. Lombardi G

    (2020) Myokines: the endocrine coupling of skeletal muscle and bone

    Advances in Clinical Chemistry 94:155–218.

    https://doi.org/10.1016/bs.acc.2019.07.010

    • PubMed
    • Google Scholar
62. 1. Gorski JP
    2. Huffman NT
    3. Vallejo J
    4. Brotto L
    5. Chittur SV
    6. Breggia A
    7. Stern A
    8. Huang J
    9. Mo C
    10. Seidah NG
    11. Bonewald L
    12. Brotto M

    (2016) Deletion of mbtps1 (pcsk8, s1p, ski-1) gene in osteocytes stimulates soleus muscle regeneration and increased size and contractile force with age

    The Journal of Biological Chemistry 291:4308–4322.

    https://doi.org/10.1074/jbc.M115.686626

    • PubMed
    • Google Scholar
63. 1. Govoni KE
    2. Wergedal JE
    3. Florin L
    4. Angel P
    5. Baylink DJ
    6. Mohan S

    (2007) Conditional deletion of insulin-like growth factor-I in collagen type 1alpha2-expressing cells results in postnatal lethality and a dramatic reduction in bone accretion

    Endocrinology 148:5706–5715.

    https://doi.org/10.1210/en.2007-0608

    • PubMed
    • Google Scholar
64. 1. Guan XX
    2. Zhou Y
    3. Li JY

    (2011) Reciprocal roles of angiotensin II and angiotensin II receptors blockade (ARB) in regulating cbfa1/RANKL via camp signaling pathway: possible mechanism for hypertension-related osteoporosis and antagonistic effect of ARB on hypertension-related osteoporosis

    International Journal of Molecular Sciences 12:4206–4213.

    https://doi.org/10.3390/ijms12074206

    • PubMed
    • Google Scholar
65. 1. Gunaratnam K
    2. Vidal C
    3. Gimble JM
    4. Duque G

    (2014) Mechanisms of palmitate-induced lipotoxicity in human osteoblasts

    Endocrinology 155:108–116.

    https://doi.org/10.1210/en.2013-1712

    • PubMed
    • Google Scholar
66. 1. Hanoun M
    2. Zhang D
    3. Mizoguchi T
    4. Pinho S
    5. Pierce H
    6. Kunisaki Y
    7. Lacombe J
    8. Armstrong SA
    9. Dührsen U
    10. Frenette PS

    (2014) Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche

    Cell Stem Cell 15:365–375.

    https://doi.org/10.1016/j.stem.2014.06.020

    • PubMed
    • Google Scholar
67. 1. Hase H
    2. Ando T
    3. Eldeiry L
    4. Brebene A
    5. Peng Y
    6. Liu L
    7. Amano H
    8. Davies TF
    9. Sun L
    10. Zaidi M
    11. Abe E

    (2006) Tnfα mediates the skeletal effects of thyroid-stimulating hormone

    PNAS 103:12849–12854.

    https://doi.org/10.1073/pnas.0600427103

    • PubMed
    • Google Scholar
68. 1. Hayashi M
    2. Nakashima T
    3. Taniguchi M
    4. Kodama T
    5. Kumanogoh A
    6. Takayanagi H

    (2012) Osteoprotection by semaphorin 3A

    Nature 485:69–74.

    https://doi.org/10.1038/nature11000

    • PubMed
    • Google Scholar
69. 1. Heemstra KA
    2. van der Deure WM
    3. Peeters RP
    4. Hamdy NA
    5. Stokkel MP
    6. Corssmit EP
    7. Romijn JA
    8. Visser TJ
    9. Smit JW

    (2008) Thyroid hormone independent associations between serum TSH levels and indicators of bone turnover in cured patients with differentiated thyroid carcinoma

    European Journal of Endocrinology 159:69–76.

    https://doi.org/10.1530/EJE-08-0038

    • PubMed
    • Google Scholar
70. 1. Hilton MJ
    2. Tu X
    3. Wu X
    4. Bai S
    5. Zhao H
    6. Kobayashi T
    7. Kronenberg HM
    8. Teitelbaum SL
    9. Ross FP
    10. Kopan R
    11. Long F

    (2008) Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation

    Nature Medicine 14:306–314.

    https://doi.org/10.1038/nm1716

    • PubMed
    • Google Scholar
71. 1. Hinoi E
    2. Gao N
    3. Jung DY
    4. Yadav V
    5. Yoshizawa T
    6. Myers MG
    7. Chua SC
    8. Kim JK
    9. Kaestner KH
    10. Karsenty G

    (2008) The sympathetic tone mediates leptin’s inhibition of insulin secretion by modulating osteocalcin bioactivity

    The Journal of Cell Biology 183:1235–1242.

    https://doi.org/10.1083/jcb.200809113

    • PubMed
    • Google Scholar
72. 1. Hong S-H
    2. Koo J-W
    3. Hwang JK
    4. Hwang Y-C
    5. Jeong I-K
    6. Ahn KJ
    7. Chung H-Y
    8. Kim D-Y

    (2013) Changes in serum osteocalcin are not associated with changes in glucose or insulin for osteoporotic patients treated with bisphosphonate

    Journal of Bone Metabolism 20:37–41.

    https://doi.org/10.11005/jbm.2013.20.1.37

    • PubMed
    • Google Scholar
73. 1. Hsu H
    2. Lacey DL
    3. Dunstan CR
    4. Solovyev I
    5. Colombero A
    6. Timms E
    7. Tan HL
    8. Elliott G
    9. Kelley MJ
    10. Sarosi I
    11. Wang L
    12. Xia XZ
    13. Elliott R
    14. Chiu L
    15. Black T
    16. Scully S
    17. Capparelli C
    18. Morony S
    19. Shimamoto G
    20. Bass MB
    21. Boyle WJ

    (1999) Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand

    PNAS 96:3540–3545.

    https://doi.org/10.1073/pnas.96.7.3540

    • PubMed
    • Google Scholar
74. 1. Huang JC
    2. Sakata T
    3. Pfleger LL
    4. Bencsik M
    5. Halloran BP
    6. Bikle DD
    7. Nissenson RA

    (2004) Pth differentially regulates expression of RANKL and OPG

    Journal of Bone and Mineral Research 19:235–244.

    https://doi.org/10.1359/JBMR.0301226

    • PubMed
    • Google Scholar
75. 1. Huang J
    2. Hsu Y-H
    3. Mo C
    4. Abreu E
    5. Kiel DP
    6. Bonewald LF
    7. Brotto M
    8. Karasik D

    (2014) METTL21C is a potential pleiotropic gene for osteoporosis and sarcopenia acting through the modulation of the NF-κB signaling pathway

    Journal of Bone and Mineral Research 29:1531–1540.

    https://doi.org/10.1002/jbmr.2200

    • PubMed
    • Google Scholar
76. 1. Huntley R
    2. Jensen E
    3. Gopalakrishnan R
    4. Mansky KC

    (2019) Bone morphogenetic proteins: their role in regulating osteoclast differentiation

    Bone Reports 10:100207.

    https://doi.org/10.1016/j.bonr.2019.100207

    • PubMed
    • Google Scholar
77. 1. Iqbal J
    2. Zaidi M

    (2005) Molecular regulation of mechanotransduction

    Biochemical and Biophysical Research Communications 328:751–755.

    https://doi.org/10.1016/j.bbrc.2004.12.087

    • PubMed
    • Google Scholar
78. 1. Iqbal J
    2. Sun L
    3. Kumar TR
    4. Blair HC
    5. Zaidi M

    (2006) Follicle-stimulating hormone stimulates TNF production from immune cells to enhance osteoblast and osteoclast formation

    PNAS 103:14925–14930.

    https://doi.org/10.1073/pnas.0606805103

    • PubMed
    • Google Scholar
79. 1. Iqbal J
    2. Sun L
    3. Zaidi M

    (2009) Coupling bone degradation to formation

    Nature Medicine 15:729–731.

    https://doi.org/10.1038/nm0709-729

    • PubMed
    • Google Scholar
80. 1. Isaksson OG
    2. Lindahl A
    3. Nilsson A
    4. Isgaard J

    (1987) Mechanism of the stimulatory effect of growth hormone on longitudinal bone growth

    Endocrine Reviews 8:426–438.

    https://doi.org/10.1210/edrv-8-4-426

    • PubMed
    • Google Scholar
81. 1. Isaksson OG
    2. Ohlsson C
    3. Nilsson A
    4. Isgaard J
    5. Lindahl A

    (1991) Regulation of cartilage growth by growth hormone and insulin-like growth factor I

    Pediatric Nephrology 5:451–453.

    https://doi.org/10.1007/BF01453680

    • PubMed
    • Google Scholar
82. 1. Ishii M
    2. Egen JG
    3. Klauschen F
    4. Meier-Schellersheim M
    5. Saeki Y
    6. Vacher J
    7. Proia RL
    8. Germain RN

    (2009) Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis

    Nature 458:524–528.

    https://doi.org/10.1038/nature07713

    • PubMed
    • Google Scholar
83. 1. Ito I
    2. Hanyu A
    3. Wayama M
    4. Goto N
    5. Katsuno Y
    6. Kawasaki S
    7. Nakajima Y
    8. Kajiro M
    9. Komatsu Y
    10. Fujimura A
    11. Hirota R
    12. Murayama A
    13. Kimura K
    14. Imamura T
    15. Yanagisawa J

    (2010) Estrogen inhibits transforming growth factor beta signaling by promoting smad2/3 degradation

    The Journal of Biological Chemistry 285:14747–14755.

    https://doi.org/10.1074/jbc.M109.093039

    • PubMed
    • Google Scholar
84. 1. Janes CH
    2. Dickson ER
    3. Okazaki R
    4. Bonde S
    5. McDonagh AF
    6. Riggs BL

    (1995) Role of hyperbilirubinemia in the impairment of osteoblast proliferation associated with cholestatic jaundice

    The Journal of Clinical Investigation 95:2581–2586.

    https://doi.org/10.1172/JCI117959

    • PubMed
    • Google Scholar
85. 1. Kajimura D
    2. Lee HW
    3. Riley KJ
    4. Arteaga-Solis E
    5. Ferron M
    6. Zhou B
    7. Clarke CJ
    8. Hannun YA
    9. DePinho RA
    10. Guo XE
    11. Mann JJ
    12. Karsenty G

    (2013) Adiponectin regulates bone mass via opposite central and peripheral mechanisms through foxo1

    Cell Metabolism 17:901–915.

    https://doi.org/10.1016/j.cmet.2013.04.009

    • PubMed
    • Google Scholar
86. 1. Kajimura D
    2. Paone R
    3. Mann JJ
    4. Karsenty G

    (2014) Foxo1 regulates dbh expression and the activity of the sympathetic nervous system in vivo

    Molecular Metabolism 3:770–777.

    https://doi.org/10.1016/j.molmet.2014.07.006

    • PubMed
    • Google Scholar
87. 1. Kaneki H
    2. Guo R
    3. Chen D
    4. Yao Z
    5. Schwarz EM
    6. Zhang YE
    7. Boyce BF
    8. Xing L

    (2006) Tumor necrosis factor promotes runx2 degradation through up-regulation of smurf1 and smurf2 in osteoblasts

    The Journal of Biological Chemistry 281:4326–4333.

    https://doi.org/10.1074/jbc.M509430200

    • PubMed
    • Google Scholar
88. 1. Karsak M
    2. Cohen-Solal M
    3. Freudenberg J
    4. Ostertag A
    5. Morieux C
    6. Kornak U
    7. Essig J
    8. Erxlebe E
    9. Bab I
    10. Kubisch C
    11. de Vernejoul M-C
    12. Zimmer A

    (2005) Cannabinoid receptor type 2 gene is associated with human osteoporosis

    Human Molecular Genetics 14:3389–3396.

    https://doi.org/10.1093/hmg/ddi370

    • PubMed
    • Google Scholar
89. 1. Katayama Y
    2. Battista M
    3. Kao WM
    4. Hidalgo A
    5. Peired AJ
    6. Thomas SA
    7. Frenette PS

    (2006) Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow

    Cell 124:407–421.

    https://doi.org/10.1016/j.cell.2005.10.041

    • PubMed
    • Google Scholar
90. 1. Kerachian MA
    2. Cournoyer D
    3. Harvey EJ
    4. Chow TY
    5. Bégin LR
    6. Nahal A
    7. Séguin C

    (2010) New insights into the pathogenesis of glucocorticoid-induced avascular necrosis: microarray analysis of gene expression in a rat model

    Arthritis Research & Therapy 12:R124.

    https://doi.org/10.1186/ar3062

    • PubMed
    • Google Scholar
91. 1. Khrimian L
    2. Obri A
    3. Ramos-Brossier M
    4. Rousseaud A
    5. Moriceau S
    6. Nicot A-S
    7. Mera P
    8. Kosmidis S
    9. Karnavas T
    10. Saudou F
    11. Gao X-B
    12. Oury F
    13. Kandel E
    14. Karsenty G

    (2017) Gpr158 mediates osteocalcin’s regulation of cognition

    The Journal of Experimental Medicine 214:2859–2873.

    https://doi.org/10.1084/jem.20171320

    • PubMed
    • Google Scholar
92. 1. Kim DJ
    2. Khang YH
    3. Koh JM
    4. Shong YK
    5. Kim GS

    (2006) Low normal TSH levels are associated with low bone mineral density in healthy postmenopausal women

    Clinical Endocrinology 64:86–90.

    https://doi.org/10.1111/j.1365-2265.2005.02422.x

    • PubMed
    • Google Scholar
93. 1. Kim B-J
    2. Lee Y-S
    3. Lee S-Y
    4. Baek W-Y
    5. Choi YJ
    6. Moon SA
    7. Lee SH
    8. Kim J-E
    9. Chang E-J
    10. Kim E-Y
    11. Yoon J
    12. Kim S-W
    13. Ryu SH
    14. Lee S-K
    15. Lorenzo JA
    16. Ahn SH
    17. Kim H
    18. Lee K-U
    19. Kim GS
    20. Koh J-M

    (2018) Osteoclast-secreted SLIT3 coordinates bone resorption and formation

    The Journal of Clinical Investigation 128:1429–1441.

    https://doi.org/10.1172/JCI91086

    • PubMed
    • Google Scholar
94. 1. Kim TY
    2. Shoback DM
    3. Black DM
    4. Rogers SJ
    5. Stewart L
    6. Carter JT
    7. Posselt AM
    8. King NJ
    9. Schafer AL

    (2020a) Increases in PYY and uncoupling of bone turnover are associated with loss of bone mass after gastric bypass surgery

    Bone 131:115115.

    https://doi.org/10.1016/j.bone.2019.115115

    • PubMed
    • Google Scholar
95. 1. Kim SM
    2. Taneja C
    3. Perez-Pena H
    4. Ryu V
    5. Gumerova A
    6. Li W
    7. Ahmad N
    8. Zhu LL
    9. Liu P
    10. Mathew M
    11. Korkmaz F
    12. Gera S
    13. Sant D
    14. Hadelia E
    15. Ievleva K
    16. Kuo TC
    17. Miyashita H
    18. Liu L
    19. Tourkova I
    20. Stanley S
    21. Lizneva D
    22. Iqbal J
    23. Sun L
    24. Tamler R
    25. Blair HC
    26. New MI
    27. Haider S
    28. Yuen T
    29. Zaidi M

    (2020b) Repurposing erectile dysfunction drugs tadalafil and vardenafil to increase bone mass

    PNAS 117:14386–14394.

    https://doi.org/10.1073/pnas.2000950117

    • PubMed
    • Google Scholar
96. 1. Kim SM
    2. Yuen T
    3. Iqbal J
    4. Rubin MR
    5. Zaidi M

    (2020c) The NO-cgmp-PKG pathway in skeletal remodeling

    Annals of the New York Academy of Sciences 1487:21–30.

    https://doi.org/10.1111/nyas.14486

    • PubMed
    • Google Scholar
97. 1. Kim SM
    2. Ryu V
    3. Miyashita S
    4. Korkmaz F
    5. Lizneva D
    6. Gera S
    7. Latif R
    8. Davies TF
    9. Iqbal J
    10. Yuen T
    11. Zaidi M

    (2021) Thyrotropin, hyperthyroidism, and bone mass

    The Journal of Clinical Endocrinology and Metabolism 106:e4809–e4821.

    https://doi.org/10.1210/clinem/dgab548

    • PubMed
    • Google Scholar
98. 1. Kleyer A
    2. Scholtysek C
    3. Bottesch E
    4. Hillienhof U
    5. Beyer C
    6. Distler JH
    7. Tuckermann JP
    8. Schett G
    9. Krönke G

    (2012) Liver X receptors orchestrate osteoblast/osteoclast crosstalk and counteract pathologic bone loss

    Journal of Bone and Mineral Research 27:2442–2451.

    https://doi.org/10.1002/jbmr.1702

    • PubMed
    • Google Scholar
99. 1. Komatsu N
    2. Okamoto K
    3. Sawa S
    4. Nakashima T
    5. Oh-hora M
    6. Kodama T
    7. Tanaka S
    8. Bluestone JA
    9. Takayanagi H

    (2014) Pathogenic conversion of Foxp3+ T cells into Th17 cells in autoimmune arthritis

    Nature Medicine 20:62–68.

    https://doi.org/10.1038/nm.3432

    • PubMed
    • Google Scholar
100. 1. Krishnan V
     2. Bryant HU
     3. Macdougald OA

     (2006) Regulation of bone mass by Wnt signaling

     The Journal of Clinical Investigation 116:1202–1209.

     https://doi.org/10.1172/JCI28551

     • PubMed
     • Google Scholar
101. 1. Kusumbe AP
     2. Ramasamy SK
     3. Adams RH

     (2014) Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone

     Nature 507:323–328.

     https://doi.org/10.1038/nature13145

     • PubMed
     • Google Scholar
102. 1. Lacey DL
     2. Timms E
     3. Tan HL
     4. Kelley MJ
     5. Dunstan CR
     6. Burgess T
     7. Elliott R
     8. Colombero A
     9. Elliott G
     10. Scully S
     11. Hsu H
     12. Sullivan J
     13. Hawkins N
     14. Davy E
     15. Capparelli C
     16. Eli A
     17. Qian YX
     18. Kaufman S
     19. Sarosi I
     20. Shalhoub V
     21. Senaldi G
     22. Guo J
     23. Delaney J
     24. Boyle WJ

     (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation

     Cell 93:165–176.

     https://doi.org/10.1016/s0092-8674(00)81569-x

     • PubMed
     • Google Scholar
103. 1. Lawal RA
     2. Zhou X
     3. Batey K
     4. Hoffman CM
     5. Georger MA
     6. Radtke F
     7. Hilton MJ
     8. Xing L
     9. Frisch BJ
     10. Calvi LM

     (2017) The notch ligand jagged1 regulates the osteoblastic lineage by maintaining the osteoprogenitor pool

     Journal of Bone and Mineral Research 32:1320–1331.

     https://doi.org/10.1002/jbmr.3106

     • PubMed
     • Google Scholar
104. 1. Le PT
     2. Liu H
     3. Alabdulaaly L
     4. Vegting Y
     5. Calle IL
     6. Gori F
     7. Lanske B
     8. Baron R
     9. Rosen CJ

     (2021) The role of zfp467 in mediating the pro-osteogenic and anti-adipogenic effects on bone and bone marrow niche

     Bone 144:115832.

     https://doi.org/10.1016/j.bone.2020.115832

     • PubMed
     • Google Scholar
105. 1. Li J-Y
     2. D’Amelio P
     3. Robinson J
     4. Walker LD
     5. Vaccaro C
     6. Luo T
     7. Tyagi AM
     8. Yu M
     9. Reott M
     10. Sassi F
     11. Buondonno I
     12. Adams J
     13. Weitzmann MN
     14. Isaia GC
     15. Pacifici R

     (2015) Il-17A is increased in humans with primary hyperparathyroidism and mediates PTH-induced bone loss in mice

     Cell Metabolism 22:799–810.

     https://doi.org/10.1016/j.cmet.2015.09.012

     • PubMed
     • Google Scholar
106. 1. Li D
     2. Liu J
     3. Guo B
     4. Liang C
     5. Dang L
     6. Lu C
     7. He X
     8. Cheung HY-S
     9. Xu L
     10. Lu C
     11. He B
     12. Liu B
     13. Shaikh AB
     14. Li F
     15. Wang L
     16. Yang Z
     17. Au DW-T
     18. Peng S
     19. Zhang Z
     20. Zhang B-T
     21. Pan X
     22. Qian A
     23. Shang P
     24. Xiao L
     25. Jiang B
     26. Wong CK-C
     27. Xu J
     28. Bian Z
     29. Liang Z
     30. Guo D-A
     31. Zhu H
     32. Tan W
     33. Lu A
     34. Zhang G

     (2016) Osteoclast-derived exosomal mir-214-3p inhibits osteoblastic bone formation

     Nature Communications 7:10872.

     https://doi.org/10.1038/ncomms10872

     • PubMed
     • Google Scholar
107. 1. Li J-Y
     2. Yu M
     3. Tyagi AM
     4. Vaccaro C
     5. Hsu E
     6. Adams J
     7. Bellido T
     8. Weitzmann MN
     9. Pacifici R

     (2019) Il-17 receptor signaling in osteoblasts/osteocytes mediates PTH-induced bone loss and enhances osteocytic RANKL production

     Journal of Bone and Mineral Research 34:349–360.

     https://doi.org/10.1002/jbmr.3600

     • PubMed
     • Google Scholar
108. 1. Liang B
     2. Feng Y

     (2012) The association of low bone mineral density with systemic inflammation in clinically stable COPD

     Endocrine 42:190–195.

     https://doi.org/10.1007/s12020-011-9583-x

     • PubMed
     • Google Scholar
109. 1. Liu X
     2. Shimono K
     3. Zhu L-L
     4. Li J
     5. Peng Y
     6. Imam A
     7. Iqbal J
     8. Moonga S
     9. Colaianni G
     10. Su C
     11. Lu Z
     12. Iwamoto M
     13. Pacifici M
     14. Zallone A
     15. Sun L
     16. Zaidi M

     (2009) Oxytocin deficiency impairs maternal skeletal remodeling

     Biochemical and Biophysical Research Communications 388:161–166.

     https://doi.org/10.1016/j.bbrc.2009.07.148

     • PubMed
     • Google Scholar
110. 1. Liu S
     2. Cheng Y
     3. Xu W
     4. Bian Z

     (2010) Protective effects of follicle-stimulating hormone inhibitor on alveolar bone loss resulting from experimental periapical lesions in ovariectomized rats

     Journal of Endodontics 36:658–663.

     https://doi.org/10.1016/j.joen.2010.01.011

     • PubMed
     • Google Scholar
111. 1. Liu P
     2. Ji Y
     3. Yuen T
     4. Rendina-Ruedy E
     5. DeMambro VE
     6. Dhawan S
     7. Abu-Amer W
     8. Izadmehr S
     9. Zhou B
     10. Shin AC
     11. Latif R
     12. Thangeswaran P
     13. Gupta A
     14. Li J
     15. Shnayder V
     16. Robinson ST
     17. Yu YE
     18. Zhang X
     19. Yang F
     20. Lu P
     21. Zhou Y
     22. Zhu L-L
     23. Oberlin DJ
     24. Davies TF
     25. Reagan MR
     26. Brown A
     27. Kumar TR
     28. Epstein S
     29. Iqbal J
     30. Avadhani NG
     31. New MI
     32. Molina H
     33. van Klinken JB
     34. Guo EX
     35. Buettner C
     36. Haider S
     37. Bian Z
     38. Sun L
     39. Rosen CJ
     40. Zaidi M

     (2017) Blocking FSH induces thermogenic adipose tissue and reduces body fat

     Nature 546:107–112.

     https://doi.org/10.1038/nature22342

     • PubMed
     • Google Scholar
112. 1. Lu W
     2. Wang W
     3. Wang S
     4. Feng Y
     5. Liu K

     (2016) Rosiglitazone promotes bone marrow adipogenesis to impair myelopoiesis under stress

     PLOS ONE 11:e0149543.

     https://doi.org/10.1371/journal.pone.0149543

     • PubMed
     • Google Scholar
113. 1. Luegmayr E
     2. Glantschnig H
     3. Wesolowski GA
     4. Gentile MA
     5. Fisher JE
     6. Rodan GA
     7. Reszka AA

     (2004) Osteoclast formation, survival and morphology are highly dependent on exogenous cholesterol/lipoproteins

     Cell Death and Differentiation 11 Suppl 1:S108–S118.

     https://doi.org/10.1038/sj.cdd.4401399

     • PubMed
     • Google Scholar
114. 1. Luo J
     2. Yang Z
     3. Ma Y
     4. Yue Z
     5. Lin H
     6. Qu G
     7. Huang J
     8. Dai W
     9. Li C
     10. Zheng C
     11. Xu L
     12. Chen H
     13. Wang J
     14. Li D
     15. Siwko S
     16. Penninger JM
     17. Ning G
     18. Xiao J
     19. Liu M

     (2016) LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption

     Nature Medicine 22:539–546.

     https://doi.org/10.1038/nm.4076

     • PubMed
     • Google Scholar
115. 1. Luo Z
     2. Shang X
     3. Zhang H
     4. Wang G
     5. Massey PA
     6. Barton SR
     7. Kevil CG
     8. Dong Y

     (2019) Notch signaling in osteogenesis, osteoclastogenesis, and angiogenesis

     The American Journal of Pathology 189:1495–1500.

     https://doi.org/10.1016/j.ajpath.2019.05.005

     • PubMed
     • Google Scholar
116. 1. Lupu F
     2. Terwilliger JD
     3. Lee K
     4. Segre GV
     5. Efstratiadis A

     (2001) Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth

     Developmental Biology 229:141–162.

     https://doi.org/10.1006/dbio.2000.9975

     • PubMed
     • Google Scholar
117. 1. Ma Z
     2. Deng C
     3. Hu W
     4. Zhou J
     5. Fan C
     6. Di S
     7. Liu D
     8. Yang Y
     9. Wang D

     (2017) Liver X receptors and their agonists: targeting for cholesterol homeostasis and cardiovascular diseases

     Current Issues in Molecular Biology 22:41–64.

     https://doi.org/10.21775/cimb.022.041

     • PubMed
     • Google Scholar
118. 1. MacDonald BT
     2. Tamai K
     3. He X

     (2009) Wnt/beta-catenin signaling: components, mechanisms, and diseases

     Developmental Cell 17:9–26.

     https://doi.org/10.1016/j.devcel.2009.06.016

     • PubMed
     • Google Scholar
119. 1. Manolagas SC

     (2010) From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis

     Endocrine Reviews 31:266–300.

     https://doi.org/10.1210/er.2009-0024

     • PubMed
     • Google Scholar
120. 1. Martini G
     2. Gennari L
     3. De Paola V
     4. Pilli T
     5. Salvadori S
     6. Merlotti D
     7. Valleggi F
     8. Campagna S
     9. Franci B
     10. Avanzati A
     11. Nuti R
     12. Pacini F

     (2008) The effects of recombinant TSH on bone turnover markers and serum osteoprotegerin and RANKL levels

     Thyroid 18:455–460.

     https://doi.org/10.1089/thy.2007.0166

     • PubMed
     • Google Scholar
121. 1. Matic I
     2. Antunovic M
     3. Brkic S
     4. Josipovic P
     5. Mihalic KC
     6. Karlak I
     7. Ivkovic A
     8. Marijanovic I

     (2016a) Expression of OCT-4 and SOX-2 in bone marrow-derived human mesenchymal stem cells during osteogenic differentiation

     Open Access Macedonian Journal of Medical Sciences 4:9–16.

     https://doi.org/10.3889/oamjms.2016.008

     • PubMed
     • Google Scholar
122. 1. Matic I
     2. Matthews BG
     3. Wang X
     4. Dyment NA
     5. Worthley DL
     6. Rowe DW
     7. Grcevic D
     8. Kalajzic I

     (2016b) Quiescent bone lining cells are a major source of osteoblasts during adulthood

     Stem Cells 34:2930–2942.

     https://doi.org/10.1002/stem.2474

     • PubMed
     • Google Scholar
123. 1. Matsushita M
     2. Hasegawa S
     3. Kitoh H
     4. Mori K
     5. Ohkawara B
     6. Yasoda A
     7. Masuda A
     8. Ishiguro N
     9. Ohno K

     (2015) Meclozine promotes longitudinal skeletal growth in transgenic mice with achondroplasia carrying a gain-of-function mutation in the FGFR3 gene

     Endocrinology 156:548–554.

     https://doi.org/10.1210/en.2014-1914

     • PubMed
     • Google Scholar
124. 1. McClung MR
     2. Lewiecki EM
     3. Cohen SB
     4. Bolognese MA
     5. Woodson GC
     6. Moffett AH
     7. Peacock M
     8. Miller PD
     9. Lederman SN
     10. Chesnut CH
     11. Lain D
     12. Kivitz AJ
     13. Holloway DL
     14. Zhang C
     15. Peterson MC
     16. Bekker PJ
     17. AMG 162 Bone Loss Study Group

     (2006) Denosumab in postmenopausal women with low bone mineral density

     The New England Journal of Medicine 354:821–831.

     https://doi.org/10.1056/NEJMoa044459

     • PubMed
     • Google Scholar
125. 1. McPherron AC
     2. Lawler AM
     3. Lee SJ

     (1997) Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member

     Nature 387:83–90.

     https://doi.org/10.1038/387083a0

     • PubMed
     • Google Scholar
126. 1. McSheehy PM
     2. Chambers TJ

     (1986) Osteoblast-like cells in the presence of parathyroid hormone release soluble factor that stimulates osteoclastic bone resorption

     Endocrinology 119:1654–1659.

     https://doi.org/10.1210/endo-119-4-1654

     • PubMed
     • Google Scholar
127. 1. Méndez-Ferrer S
     2. Lucas D
     3. Battista M
     4. Frenette PS

     (2008) Haematopoietic stem cell release is regulated by circadian oscillations

     Nature 452:442–447.

     https://doi.org/10.1038/nature06685

     • PubMed
     • Google Scholar
128. 1. Méndez-Ferrer S
     2. Michurina TV
     3. Ferraro F
     4. Mazloom AR
     5. Macarthur BD
     6. Lira SA
     7. Scadden DT
     8. Ma’ayan A
     9. Enikolopov GN
     10. Frenette PS

     (2010) Mesenchymal and haematopoietic stem cells form a unique bone marrow niche

     Nature 466:829–834.

     https://doi.org/10.1038/nature09262

     • PubMed
     • Google Scholar
129. 1. Mera P
     2. Laue K
     3. Ferron M
     4. Confavreux C
     5. Wei J
     6. Galán-Díez M
     7. Lacampagne A
     8. Mitchell SJ
     9. Mattison JA
     10. Chen Y
     11. Bacchetta J
     12. Szulc P
     13. Kitsis RN
     14. de Cabo R
     15. Friedman RA
     16. Torsitano C
     17. McGraw TE
     18. Puchowicz M
     19. Kurland I
     20. Karsenty G

     (2016a) Osteocalcin signaling in myofibers is necessary and sufficient for optimum adaptation to exercise

     Cell Metabolism 23:1078–1092.

     https://doi.org/10.1016/j.cmet.2016.05.004

     • PubMed
     • Google Scholar
130. 1. Mera P
     2. Laue K
     3. Wei J
     4. Berger JM
     5. Karsenty G

     (2016b) Osteocalcin is necessary and sufficient to maintain muscle mass in older mice

     Molecular Metabolism 5:1042–1047.

     https://doi.org/10.1016/j.molmet.2016.07.002

     • PubMed
     • Google Scholar
131. 1. Møller AMJ
     2. Delaissé J-M
     3. Olesen JB
     4. Madsen JS
     5. Canto LM
     6. Bechmann T
     7. Rogatto SR
     8. Søe K

     (2020) Aging and menopause reprogram osteoclast precursors for aggressive bone resorption

     Bone Research 8:27.

     https://doi.org/10.1038/s41413-020-0102-7

     • PubMed
     • Google Scholar
132. 1. Morgan I
     2. Coulombe JC
     3. Larsen M
     4. Liu Z
     5. Ferguson VL
     6. Kumar TR

     (2022) VISIONS: FSH and bone microarchitecture in mice

     Molecular Reproduction and Development 89:315.

     https://doi.org/10.1002/mrd.23629

     • PubMed
     • Google Scholar
133. 1. Morris MS

     (2007) The association between serum thyroid-stimulating hormone in its reference range and bone status in postmenopausal american women

     Bone 40:1128–1134.

     https://doi.org/10.1016/j.bone.2006.12.001

     • PubMed
     • Google Scholar
134. 1. Nakashima T
     2. Hayashi M
     3. Fukunaga T
     4. Kurata K
     5. Oh-Hora M
     6. Feng JQ
     7. Bonewald LF
     8. Kodama T
     9. Wutz A
     10. Wagner EF
     11. Penninger JM
     12. Takayanagi H

     (2011) Evidence for osteocyte regulation of bone homeostasis through RANKL expression

     Nature Medicine 17:1231–1234.

     https://doi.org/10.1038/nm.2452

     • PubMed
     • Google Scholar
135. 1. Nakatani T
     2. Sarraj B
     3. Ohnishi M
     4. Densmore MJ
     5. Taguchi T
     6. Goetz R
     7. Mohammadi M
     8. Lanske B
     9. Razzaque MS

     (2009) In vivo genetic evidence for klotho-dependent, fibroblast growth factor 23 (fgf23) -mediated regulation of systemic phosphate homeostasis

     FASEB Journal 23:433–441.

     https://doi.org/10.1096/fj.08-114397

     • PubMed
     • Google Scholar
136. 1. Negishi-Koga T
     2. Shinohara M
     3. Komatsu N
     4. Bito H
     5. Kodama T
     6. Friedel RH
     7. Takayanagi H

     (2011) Suppression of bone formation by osteoclastic expression of semaphorin 4D

     Nature Medicine 17:1473–1480.

     https://doi.org/10.1038/nm.2489

     • PubMed
     • Google Scholar
137. 1. Ninkovic M
     2. Love S
     3. Tom BDM
     4. Bearcroft PWP
     5. Alexander GJM
     6. Compston JE

     (2002) Lack of effect of intravenous pamidronate on fracture incidence and bone mineral density after orthotopic liver transplantation

     Journal of Hepatology 37:93–100.

     https://doi.org/10.1016/s0168-8278(02)00100-9

     • PubMed
     • Google Scholar
138. 1. Obri A
     2. Khrimian L
     3. Karsenty G
     4. Oury F

     (2018) Osteocalcin in the brain: from embryonic development to age-related decline in cognition

     Nature Reviews. Endocrinology 14:174–182.

     https://doi.org/10.1038/nrendo.2017.181

     • PubMed
     • Google Scholar
139. 1. Ofek O
     2. Karsak M
     3. Leclerc N
     4. Fogel M
     5. Frenkel B
     6. Wright K
     7. Tam J
     8. Attar-Namdar M
     9. Kram V
     10. Shohami E
     11. Mechoulam R
     12. Zimmer A
     13. Bab I

     (2006) Peripheral cannabinoid receptor, CB2, regulates bone mass

     PNAS 103:696–701.

     https://doi.org/10.1073/pnas.0504187103

     • PubMed
     • Google Scholar
140. 1. Ohlsson C
     2. Bengtsson BA
     3. Isaksson OG
     4. Andreassen TT
     5. Slootweg MC

     (1998) Growth hormone and bone

     Endocrine Reviews 19:55–79.

     https://doi.org/10.1210/edrv.19.1.0324

     • PubMed
     • Google Scholar
141. 1. Ohlsson C
     2. Mohan S
     3. Sjögren K
     4. Tivesten A
     5. Isgaard J
     6. Isaksson O
     7. Jansson J-O
     8. Svensson J

     (2009) The role of liver-derived insulin-like growth factor-I

     Endocrine Reviews 30:494–535.

     https://doi.org/10.1210/er.2009-0010

     • PubMed
     • Google Scholar
142. 1. Oishi Y
     2. Manabe I

     (2020) Organ system crosstalk in cardiometabolic disease in the age of multimorbidity

     Frontiers in Cardiovascular Medicine 7:64.

     https://doi.org/10.3389/fcvm.2020.00064

     • PubMed
     • Google Scholar
143. 1. Otero K
     2. Shinohara M
     3. Zhao H
     4. Cella M
     5. Gilfillan S
     6. Colucci A
     7. Faccio R
     8. Ross FP
     9. Teitelbaum SL
     10. Takayanagi H
     11. Colonna M

     (2012) Trem2 and β-catenin regulate bone homeostasis by controlling the rate of osteoclastogenesis

     Journal of Immunology 188:2612–2621.

     https://doi.org/10.4049/jimmunol.1102836

     • PubMed
     • Google Scholar
144. 1. Oury F
     2. Khrimian L
     3. Denny CA
     4. Gardin A
     5. Chamouni A
     6. Goeden N
     7. Huang Y
     8. Lee H
     9. Srinivas P
     10. Gao X-B
     11. Suyama S
     12. Langer T
     13. Mann JJ
     14. Horvath TL
     15. Bonnin A
     16. Karsenty G

     (2013) Maternal and offspring pools of osteocalcin influence brain development and functions

     Cell 155:228–241.

     https://doi.org/10.1016/j.cell.2013.08.042

     • PubMed
     • Google Scholar
145. 1. Pállinger E
     2. Csaba G

     (2008) A hormone map of human immune cells showing the presence of adrenocorticotropic hormone, triiodothyronine and endorphin in immunophenotyped white blood cells

     Immunology 123:584–589.

     https://doi.org/10.1111/j.1365-2567.2007.02731.x

     • PubMed
     • Google Scholar
146. 1. Pederson L
     2. Ruan M
     3. Westendorf JJ
     4. Khosla S
     5. Oursler MJ

     (2008) Regulation of bone formation by osteoclasts involves wnt/BMP signaling and the chemokine sphingosine-1-phosphate

     PNAS 105:20764–20769.

     https://doi.org/10.1073/pnas.0805133106

     • PubMed
     • Google Scholar
147. 1. Pfeilschifter J
     2. Chenu C
     3. Bird A
     4. Mundy GR
     5. Roodman GD

     (1989) Interleukin-1 and tumor necrosis factor stimulate the formation of human osteoclastlike cells in vitro

     Journal of Bone and Mineral Research 4:113–118.

     https://doi.org/10.1002/jbmr.5650040116

     • PubMed
     • Google Scholar
148. 1. Pi Min
     2. Chen L
     3. Huang M-Z
     4. Zhu W
     5. Ringhofer B
     6. Luo J
     7. Christenson L
     8. Li B
     9. Zhang J
     10. Jackson PD
     11. Faber P
     12. Brunden KR
     13. Harrington JJ
     14. Quarles LD

     (2008) Gprc6A null mice exhibit osteopenia, feminization and metabolic syndrome

     PLOS ONE 3:e3858.

     https://doi.org/10.1371/journal.pone.0003858

     • PubMed
     • Google Scholar
149. 1. Pi M.
     2. Wu Y
     3. Quarles LD

     (2011) Gprc6A mediates responses to osteocalcin in β-cells in vitro and pancreas in vivo

     Journal of Bone and Mineral Research 26:1680–1683.

     https://doi.org/10.1002/jbmr.390

     • PubMed
     • Google Scholar
150. 1. Pierce JL
     2. Begun DL
     3. Westendorf JJ
     4. McGee-Lawrence ME

     (2019) Defining osteoblast and adipocyte lineages in the bone marrow

     Bone 118:2–7.

     https://doi.org/10.1016/j.bone.2018.05.019

     • PubMed
     • Google Scholar
151. 1. Qiang Y-W
     2. Chen Y
     3. Stephens O
     4. Brown N
     5. Chen B
     6. Epstein J
     7. Barlogie B
     8. Shaughnessy JD

     (2008) Myeloma-derived dickkopf-1 disrupts wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma

     Blood 112:196–207.

     https://doi.org/10.1182/blood-2008-01-132134

     • PubMed
     • Google Scholar
152. 1. Qin W
     2. Sun L
     3. Cao J
     4. Peng Y
     5. Collier L
     6. Wu Y
     7. Creasey G
     8. Li J
     9. Qin Y
     10. Jarvis J
     11. Bauman WA
     12. Zaidi M
     13. Cardozo C

     (2013) The central nervous system (CNS)-independent anti-bone-resorptive activity of muscle contraction and the underlying molecular and cellular signatures

     The Journal of Biological Chemistry 288:13511–13521.

     https://doi.org/10.1074/jbc.M113.454892

     • PubMed
     • Google Scholar
153. 1. Qin Y
     2. Peng Y
     3. Zhao W
     4. Pan J
     5. Ksiezak-Reding H
     6. Cardozo C
     7. Wu Y
     8. Divieti Pajevic P
     9. Bonewald LF
     10. Bauman WA
     11. Qin W

     (2017) Myostatin inhibits osteoblastic differentiation by suppressing osteocyte-derived exosomal microrna-218: A novel mechanism in muscle-bone communication

     The Journal of Biological Chemistry 292:11021–11033.

     https://doi.org/10.1074/jbc.M116.770941

     • PubMed
     • Google Scholar
154. 1. Quach JM
     2. Walker EC
     3. Allan E
     4. Solano M
     5. Yokoyama A
     6. Kato S
     7. Sims NA
     8. Gillespie MT
     9. Martin TJ

     (2011) Zinc finger protein 467 is a novel regulator of osteoblast and adipocyte commitment

     The Journal of Biological Chemistry 286:4186–4198.

     https://doi.org/10.1074/jbc.M110.178251

     • PubMed
     • Google Scholar
155. 1. Ramajayam G
     2. Vignesh RC
     3. Karthikeyan S
     4. Kumar KS
     5. Karthikeyan GD
     6. Veni S
     7. Sridhar M
     8. Arunakaran J
     9. Aruldhas MM
     10. Srinivasan N

     (2012) Regulation of insulin-like growth factors and their binding proteins by thyroid stimulating hormone in human osteoblast-like (saos2) cells

     Molecular and Cellular Biochemistry 368:77–88.

     https://doi.org/10.1007/s11010-012-1345-4

     • PubMed
     • Google Scholar
156. 1. Randolph JF Jr
     2. Sowers M
     3. Gold EB
     4. Mohr BA
     5. Luborsky J
     6. Santoro N
     7. McConnell DS
     8. Finkelstein JS
     9. Korenman SG
     10. Matthews KA
     11. Sternfeld B
     12. Lasley BL

     (2003) Reproductive hormones in the early menopausal transition: relationship to ethnicity, body size, and menopausal status

     The Journal of Clinical Endocrinology and Metabolism 88:1516–1522.

     https://doi.org/10.1210/jc.2002-020777

     • PubMed
     • Google Scholar
157. 1. Rankin EB
     2. Wu C
     3. Khatri R
     4. Wilson TLS
     5. Andersen R
     6. Araldi E
     7. Rankin AL
     8. Yuan J
     9. Kuo CJ
     10. Schipani E
     11. Giaccia AJ

     (2012) The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO

     Cell 149:63–74.

     https://doi.org/10.1016/j.cell.2012.01.051

     • PubMed
     • Google Scholar
158. 1. Rauner M
     2. Sipos W
     3. Pietschmann P

     (2008) Age-dependent wnt gene expression in bone and during the course of osteoblast differentiation

     Age 30:273–282.

     https://doi.org/10.1007/s11357-008-9069-9

     • PubMed
     • Google Scholar
159. 1. Reid IR
     2. Lucas J
     3. Wattie D
     4. Horne A
     5. Bolland M
     6. Gamble GD
     7. Davidson JS
     8. Grey AB

     (2005) Effects of a beta-blocker on bone turnover in normal postmenopausal women: a randomized controlled trial

     The Journal of Clinical Endocrinology and Metabolism 90:5212–5216.

     https://doi.org/10.1210/jc.2005-0573

     • PubMed
     • Google Scholar
160. 1. Rendina D
     2. Gianfrancesco F
     3. De Filippo G
     4. Merlotti D
     5. Esposito T
     6. Mingione A
     7. Nuti R
     8. Strazzullo P
     9. Mossetti G
     10. Gennari L

     (2010) Fshr gene polymorphisms influence bone mineral density and bone turnover in postmenopausal women

     European Journal of Endocrinology 163:165–172.

     https://doi.org/10.1530/EJE-10-0043

     • PubMed
     • Google Scholar
161. 1. Rivadeneira F
     2. Styrkársdottir U
     3. Estrada K
     4. Halldórsson BV
     5. Hsu Y-H
     6. Richards JB
     7. Zillikens MC
     8. Kavvoura FK
     9. Amin N
     10. Aulchenko YS
     11. Cupples LA
     12. Deloukas P
     13. Demissie S
     14. Grundberg E
     15. Hofman A
     16. Kong A
     17. Karasik D
     18. van Meurs JB
     19. Oostra B
     20. Pastinen T
     21. Pols HAP
     22. Sigurdsson G
     23. Soranzo N
     24. Thorleifsson G
     25. Thorsteinsdottir U
     26. Williams FMK
     27. Wilson SG
     28. Zhou Y
     29. Ralston SH
     30. van Duijn CM
     31. Spector T
     32. Kiel DP
     33. Stefansson K
     34. Ioannidis JPA
     35. Uitterlinden AG
     36. Genetic Factors for Osteoporosis (GEFOS) Consortium

     (2009) Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies

     Nature Genetics 41:1199–1206.

     https://doi.org/10.1038/ng.446

     • PubMed
     • Google Scholar
162. 1. Robinson LJ
     2. Tourkova I
     3. Wang Y
     4. Sharrow AC
     5. Landau MS
     6. Yaroslavskiy BB
     7. Sun L
     8. Zaidi M
     9. Blair HC

     (2010) FSH-receptor isoforms and FSH-dependent gene transcription in human monocytes and osteoclasts

     Biochemical and Biophysical Research Communications 394:12–17.

     https://doi.org/10.1016/j.bbrc.2010.02.112

     • PubMed
     • Google Scholar
163. 1. Roman-Garcia P
     2. Quiros-Gonzalez I
     3. Mottram L
     4. Lieben L
     5. Sharan K
     6. Wangwiwatsin A
     7. Tubio J
     8. Lewis K
     9. Wilkinson D
     10. Santhanam B
     11. Sarper N
     12. Clare S
     13. Vassiliou GS
     14. Velagapudi VR
     15. Dougan G
     16. Yadav VK

     (2014) Vitamin B₁₂-dependent taurine synthesis regulates growth and bone mass

     The Journal of Clinical Investigation 124:2988–3002.

     https://doi.org/10.1172/JCI72606

     • PubMed
     • Google Scholar
164. 1. Ruiz-Gaspà S
     2. Martinez-Ferrer A
     3. Guañabens N
     4. Dubreuil M
     5. Peris P
     6. Enjuanes A
     7. Martinez de Osaba MJ
     8. Alvarez L
     9. Monegal A
     10. Combalia A
     11. Parés A

     (2011) Effects of bilirubin and sera from jaundiced patients on osteoblasts: contribution to the development of osteoporosis in liver diseases

     Hepatology 54:2104–2113.

     https://doi.org/10.1002/hep.24605

     • PubMed
     • Google Scholar
165. 1. Saag KG
     2. Petersen J
     3. Brandi ML
     4. Karaplis AC
     5. Lorentzon M
     6. Thomas T
     7. Maddox J
     8. Fan M
     9. Meisner PD
     10. Grauer A

     (2017) Romosozumab or alendronate for fracture prevention in women with osteoporosis

     The New England Journal of Medicine 377:1417–1427.

     https://doi.org/10.1056/NEJMoa1708322

     • PubMed
     • Google Scholar
166. 1. Sadeghi F
     2. Vahednia E
     3. Naderi Meshkin H
     4. Kerachian MA

     (2020) The effect of adrenocorticotropic hormone on alpha-2-macroglobulin in osteoblasts derived from human mesenchymal stem cells

     Journal of Cellular and Molecular Medicine 24:4784–4790.

     https://doi.org/10.1111/jcmm.15152

     • PubMed
     • Google Scholar
167. 1. Salazar VS
     2. Gamer LW
     3. Rosen V

     (2016) BMP signalling in skeletal development, disease and repair

     Nature Reviews. Endocrinology 12:203–221.

     https://doi.org/10.1038/nrendo.2016.12

     • PubMed
     • Google Scholar
168. 1. Sampath TK
     2. Simic P
     3. Sendak R
     4. Draca N
     5. Bowe AE
     6. O’Brien S
     7. Schiavi SC
     8. McPherson JM
     9. Vukicevic S

     (2007) Thyroid-stimulating hormone restores bone volume, microarchitecture, and strength in aged ovariectomized rats

     Journal of Bone and Mineral Research 22:849–859.

     https://doi.org/10.1359/jbmr.070302

     • PubMed
     • Google Scholar
169. 1. Sato S
     2. Hanada R
     3. Kimura A
     4. Abe T
     5. Matsumoto T
     6. Iwasaki M
     7. Inose H
     8. Ida T
     9. Mieda M
     10. Takeuchi Y
     11. Fukumoto S
     12. Fujita T
     13. Kato S
     14. Kangawa K
     15. Kojima M
     16. Shinomiya K
     17. Takeda S

     (2007) Central control of bone remodeling by neuromedin U

     Nature Medicine 13:1234–1240.

     https://doi.org/10.1038/nm1640

     • PubMed
     • Google Scholar
170. 1. Schipani E
     2. Maes C
     3. Carmeliet G
     4. Semenza GL

     (2009) Regulation of osteogenesis-angiogenesis coupling by hifs and VEGF

     Journal of Bone and Mineral Research 24:1347–1353.

     https://doi.org/10.1359/jbmr.090602

     • PubMed
     • Google Scholar
171. 1. Schlienger RG
     2. Kraenzlin ME
     3. Jick SS
     4. Meier CR

     (2004) Use of beta-blockers and risk of fractures

     JAMA 292:1326–1332.

     https://doi.org/10.1001/jama.292.11.1326

     • PubMed
     • Google Scholar
172. 1. Schroder EA
     2. Harfmann BD
     3. Zhang X
     4. Srikuea R
     5. England JH
     6. Hodge BA
     7. Wen Y
     8. Riley LA
     9. Yu Q
     10. Christie A
     11. Smith JD
     12. Seward T
     13. Wolf Horrell EM
     14. Mula J
     15. Peterson CA
     16. Butterfield TA
     17. Esser KA

     (2015) Intrinsic muscle clock is necessary for musculoskeletal health

     The Journal of Physiology 593:5387–5404.

     https://doi.org/10.1113/JP271436

     • PubMed
     • Google Scholar
173. 1. Seriwatanachai D
     2. Thongchote K
     3. Charoenphandhu N
     4. Pandaranandaka J
     5. Tudpor K
     6. Teerapornpuntakit J
     7. Suthiphongchai T
     8. Krishnamra N

     (2008) Prolactin directly enhances bone turnover by raising osteoblast-expressed receptor activator of nuclear factor kappaB ligand/osteoprotegerin ratio

     Bone 42:535–546.

     https://doi.org/10.1016/j.bone.2007.11.008

     • PubMed
     • Google Scholar
174. 1. Shah TA
     2. Rogers MB

     (2018) Unanswered questions regarding sex and BMP/TGF-β signaling

     Journal of Developmental Biology 6:14.

     https://doi.org/10.3390/jdb6020014

     • PubMed
     • Google Scholar
175. 1. Shen R
     2. Chen M
     3. Wang Y-J
     4. Kaneki H
     5. Xing L
     6. O’keefe RJ
     7. Chen D

     (2006) Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation

     The Journal of Biological Chemistry 281:3569–3576.

     https://doi.org/10.1074/jbc.M506761200

     • PubMed
     • Google Scholar
176. 1. Shi YC
     2. Baldock PA

     (2012) Central and peripheral mechanisms of the NPY system in the regulation of bone and adipose tissue

     Bone 50:430–436.

     https://doi.org/10.1016/j.bone.2011.10.001

     • PubMed
     • Google Scholar
177. 1. Shimada T
     2. Mizutani S
     3. Muto T
     4. Yoneya T
     5. Hino R
     6. Takeda S
     7. Takeuchi Y
     8. Fujita T
     9. Fukumoto S
     10. Yamashita T

     (2001) Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia

     PNAS 98:6500–6505.

     https://doi.org/10.1073/pnas.101545198

     • PubMed
     • Google Scholar
178. 1. Shimada T
     2. Kakitani M
     3. Yamazaki Y
     4. Hasegawa H
     5. Takeuchi Y
     6. Fujita T
     7. Fukumoto S
     8. Tomizuka K
     9. Yamashita T

     (2004) Targeted ablation of FGF23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism

     The Journal of Clinical Investigation 113:561–568.

     https://doi.org/10.1172/JCI19081

     • PubMed
     • Google Scholar
179. 1. Shooshtarizadeh P
     2. Helness A
     3. Vadnais C
     4. Brouwer N
     5. Beauchemin H
     6. Chen R
     7. Bagci H
     8. Staal FJT
     9. Coté J-F
     10. Möröy T

     (2019) Gfi1b regulates the level of wnt/β-catenin signaling in hematopoietic stem cells and megakaryocytes

     Nature Communications 10:1270.

     https://doi.org/10.1038/s41467-019-09273-z

     • PubMed
     • Google Scholar
180. 1. Simonet WS
     2. Lacey DL
     3. Dunstan CR
     4. Kelley M
     5. Chang MS
     6. Lüthy R
     7. Nguyen HQ
     8. Wooden S
     9. Bennett L
     10. Boone T
     11. Shimamoto G
     12. DeRose M
     13. Elliott R
     14. Colombero A
     15. Tan HL
     16. Trail G
     17. Sullivan J
     18. Davy E
     19. Bucay N
     20. Renshaw-Gegg L
     21. Hughes TM
     22. Hill D
     23. Pattison W
     24. Campbell P
     25. Sander S
     26. Van G
     27. Tarpley J
     28. Derby P
     29. Lee R
     30. Boyle WJ

     (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density

     Cell 89:309–319.

     https://doi.org/10.1016/s0092-8674(00)80209-3

     • PubMed
     • Google Scholar
181. 1. Sjögren K
     2. Liu JL
     3. Blad K
     4. Skrtic S
     5. Vidal O
     6. Wallenius V
     7. LeRoith D
     8. Törnell J
     9. Isaksson OG
     10. Jansson JO
     11. Ohlsson C

     (1999) Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice

     PNAS 96:7088–7092.

     https://doi.org/10.1073/pnas.96.12.7088

     • PubMed
     • Google Scholar
182. 1. Sowers M
     2. Eyre D
     3. Hollis BW
     4. Randolph JF
     5. Shapiro B
     6. Jannausch ML
     7. Crutchfield M

     (1995) Biochemical markers of bone turnover in lactating and nonlactating postpartum women

     The Journal of Clinical Endocrinology and Metabolism 80:2210–2216.

     https://doi.org/10.1210/jcem.80.7.7608281

     • PubMed
     • Google Scholar
183. 1. Sowers MR
     2. Greendale GA
     3. Bondarenko I
     4. Finkelstein JS
     5. Cauley JA
     6. Neer RM
     7. Ettinger B

     (2003) Endogenous hormones and bone turnover markers in pre- and perimenopausal women: Swan

     Osteoporosis International 14:191–197.

     https://doi.org/10.1007/s00198-002-1329-4

     • PubMed
     • Google Scholar
184. 1. Stachnik A
     2. Yuen T
     3. Iqbal J
     4. Sgobba M
     5. Gupta Y
     6. Lu P
     7. Colaianni G
     8. Ji Y
     9. Zhu LL
     10. Kim SM
     11. Li J
     12. Liu P
     13. Izadmehr S
     14. Sangodkar J
     15. Scherer T
     16. Mujtaba S
     17. Galsky M
     18. Gomez J
     19. Epstein S
     20. Buettner C
     21. Bian Z
     22. Zallone A
     23. Aggarwal AK
     24. Haider S
     25. New MI
     26. Sun L
     27. Narla G
     28. Zaidi M

     (2014) Repurposing of bisphosphonates for the prevention and therapy of nonsmall cell lung and breast cancer

     PNAS 111:17995–18000.

     https://doi.org/10.1073/pnas.1421422111

     • PubMed
     • Google Scholar
185. 1. Stratikopoulos E
     2. Szabolcs M
     3. Dragatsis I
     4. Klinakis A
     5. Efstratiadis A

     (2008) The hormonal action of IGF1 in postnatal mouse growth

     PNAS 105:19378–19383.

     https://doi.org/10.1073/pnas.0809223105

     • PubMed
     • Google Scholar
186. 1. Suchacki KJ
     2. Cawthorn WP
     3. Rosen CJ

     (2016) Bone marrow adipose tissue: formation, function and regulation

     Current Opinion in Pharmacology 28:50–56.

     https://doi.org/10.1016/j.coph.2016.03.001

     • PubMed
     • Google Scholar
187. 1. Sun L
     2. Blair HC
     3. Peng Y
     4. Zaidi N
     5. Adebanjo OA
     6. Wu XB
     7. Wu XY
     8. Iqbal J
     9. Epstein S
     10. Abe E
     11. Moonga BS
     12. Zaidi M

     (2005) Calcineurin regulates bone formation by the osteoblast

     PNAS 102:17130–17135.

     https://doi.org/10.1073/pnas.0508480102

     • PubMed
     • Google Scholar
188. 1. Sun L
     2. Peng Y
     3. Sharrow AC
     4. Iqbal J
     5. Zhang Z
     6. Papachristou DJ
     7. Zaidi S
     8. Zhu L-L
     9. Yaroslavskiy BB
     10. Zhou H
     11. Zallone A
     12. Sairam MR
     13. Kumar TR
     14. Bo W
     15. Braun J
     16. Cardoso-Landa L
     17. Schaffler MB
     18. Moonga BS
     19. Blair HC
     20. Zaidi M

     (2006) Fsh directly regulates bone mass

     Cell 125:247–260.

     https://doi.org/10.1016/j.cell.2006.01.051

     • PubMed
     • Google Scholar
189. 1. Sun L
     2. Peng Y
     3. Zaidi N
     4. Zhu LL
     5. Iqbal J
     6. Yamoah K
     7. Wang X
     8. Liu P
     9. Abe E
     10. Moonga BS
     11. Epstein S
     12. Zaidi M

     (2007) Evidence that calcineurin is required for the genesis of bone-resorbing osteoclasts

     American Journal of Physiology. Renal Physiology 292:F285–F291.

     https://doi.org/10.1152/ajprenal.00415.2005

     • PubMed
     • Google Scholar
190. 1. Sun L
     2. Vukicevic S
     3. Baliram R
     4. Yang G
     5. Sendak R
     6. McPherson J
     7. Zhu LL
     8. Iqbal J
     9. Latif R
     10. Natrajan A
     11. Arabi A
     12. Yamoah K
     13. Moonga BS
     14. Gabet Y
     15. Davies TF
     16. Bab I
     17. Abe E
     18. Sampath K
     19. Zaidi M

     (2008) Intermittent recombinant TSH injections prevent ovariectomy-induced bone loss

     PNAS 105:4289–4294.

     https://doi.org/10.1073/pnas.0712395105

     • PubMed
     • Google Scholar
191. 1. Sun L
     2. Zhu LL
     3. Lu P
     4. Yuen T
     5. Li J
     6. Ma R
     7. Baliram R
     8. Moonga SS
     9. Liu P
     10. Zallone A
     11. New MI
     12. Davies TF
     13. Zaidi M

     (2013) Genetic confirmation for a central role for tnfα in the direct action of thyroid stimulating hormone on the skeleton

     PNAS 110:9891–9896.

     https://doi.org/10.1073/pnas.1308336110

     • PubMed
     • Google Scholar
192. 1. Sun L
     2. Tamma R
     3. Yuen T
     4. Colaianni G
     5. Ji Y
     6. Cuscito C
     7. Bailey J
     8. Dhawan S
     9. Lu P
     10. Calvano CD
     11. Zhu LL
     12. Zambonin CG
     13. Di Benedetto A
     14. Stachnik A
     15. Liu P
     16. Grano M
     17. Colucci S
     18. Davies TF
     19. New MI
     20. Zallone A
     21. Zaidi M

     (2016) Functions of vasopressin and oxytocin in bone mass regulation

     PNAS 113:164–169.

     https://doi.org/10.1073/pnas.1523762113

     • PubMed
     • Google Scholar
193. 1. Sun L
     2. Lizneva D
     3. Ji Y
     4. Colaianni G
     5. Hadelia E
     6. Gumerova A
     7. Ievleva K
     8. Kuo TC
     9. Korkmaz F
     10. Ryu V
     11. Rahimova A
     12. Gera S
     13. Taneja C
     14. Khan A
     15. Ahmad N
     16. Tamma R
     17. Bian Z
     18. Zallone A
     19. Kim SM
     20. New MI
     21. Iqbal J
     22. Yuen T
     23. Zaidi M

     (2019) Oxytocin regulates body composition

     PNAS 116:26808–26815.

     https://doi.org/10.1073/pnas.1913611116

     • PubMed
     • Google Scholar
194. 1. Takayanagi H

     (2007) Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems

     Nature Reviews. Immunology 7:292–304.

     https://doi.org/10.1038/nri2062

     • PubMed
     • Google Scholar
195. 1. Takeda S
     2. Elefteriou F
     3. Levasseur R
     4. Liu X
     5. Zhao L
     6. Parker KL
     7. Armstrong D
     8. Ducy P
     9. Karsenty G

     (2002) Leptin regulates bone formation via the sympathetic nervous system

     Cell 111:305–317.

     https://doi.org/10.1016/s0092-8674(02)01049-8

     • PubMed
     • Google Scholar
196. 1. Tam J
     2. Trembovler V
     3. Di Marzo V
     4. Petrosino S
     5. Leo G
     6. Alexandrovich A
     7. Regev E
     8. Casap N
     9. Shteyer A
     10. Ledent C
     11. Karsak M
     12. Zimmer A
     13. Mechoulam R
     14. Yirmiya R
     15. Shohami E
     16. Bab I

     (2008) The cannabinoid CB1 receptor regulates bone formation by modulating adrenergic signaling

     FASEB Journal 22:285–294.

     https://doi.org/10.1096/fj.06-7957com

     • PubMed
     • Google Scholar
197. 1. Tamma R
     2. Colaianni G
     3. Zhu L
     4. DiBenedetto A
     5. Greco G
     6. Montemurro G
     7. Patano N
     8. Strippoli M
     9. Vergari R
     10. Mancini L
     11. Colucci S
     12. Grano M
     13. Faccio R
     14. Liu X
     15. Li J
     16. Usmani S
     17. Bachar M
     18. Bab I
     19. Nishimori K
     20. Young LJ
     21. Buettner C
     22. Iqbal J
     23. Sun L
     24. Zaidi M
     25. Zallone A

     (2009) Oxytocin is an anabolic bone hormone

     PNAS 106:7149–7154.

     https://doi.org/10.1073/pnas.0901890106

     • PubMed
     • Google Scholar
198. 1. Tamma R
     2. Sun L
     3. Cuscito C
     4. Lu P
     5. Corcelli M
     6. Li J
     7. Colaianni G
     8. Moonga SS
     9. Di Benedetto A
     10. Grano M
     11. Colucci S
     12. Yuen T
     13. New MI
     14. Zallone A
     15. Zaidi M

     (2013) Regulation of bone remodeling by vasopressin explains the bone loss in hyponatremia

     PNAS 110:18644–18649.

     https://doi.org/10.1073/pnas.1318257110

     • PubMed
     • Google Scholar
199. 1. Tang Y
     2. Wu X
     3. Lei W
     4. Pang L
     5. Wan C
     6. Shi Z
     7. Zhao L
     8. Nagy TR
     9. Peng X
     10. Hu J
     11. Feng X
     12. Van Hul W
     13. Wan M
     14. Cao X

     (2009) TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation

     Nature Medicine 15:757–765.

     https://doi.org/10.1038/nm.1979

     • PubMed
     • Google Scholar
200. 1. Tencerova M
     2. Kassem M

     (2016) The bone marrow-derived stromal cells: commitment and regulation of adipogenesis

     Frontiers in Endocrinology 7:127.

     https://doi.org/10.3389/fendo.2016.00127

     • PubMed
     • Google Scholar
201. 1. Thrailkill KM
     2. Jo CH
     3. Cockrell GE
     4. Moreau CS
     5. Lumpkin CK
     6. Fowlkes JL

     (2012) Determinants of undercarboxylated and carboxylated osteocalcin concentrations in type 1 diabetes

     Osteoporosis International 23:1799–1806.

     https://doi.org/10.1007/s00198-011-1807-7

     • PubMed
     • Google Scholar
202. 1. Tsuchida A
     2. Yamauchi T
     3. Takekawa S
     4. Hada Y
     5. Ito Y
     6. Maki T
     7. Kadowaki T

     (2005) Peroxisome proliferator-activated receptor (PPAR) alpha activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue: comparison of activation of PPARalpha, PPARgamma, and their combination

     Diabetes 54:3358–3370.

     https://doi.org/10.2337/diabetes.54.12.3358

     • PubMed
     • Google Scholar
203. 1. van der Deure WM
     2. Uitterlinden AG
     3. Hofman A
     4. Rivadeneira F
     5. Pols HAP
     6. Peeters RP
     7. Visser TJ

     (2008) Effects of serum TSH and FT4 levels and the TSHR-asp727glu polymorphism on bone: the rotterdam study

     Clinical Endocrinology 68:175–181.

     https://doi.org/10.1111/j.1365-2265.2007.03016.x

     • PubMed
     • Google Scholar
204. 1. Veldhuis-Vlug AG
     2. Woods GN
     3. Sigurdsson S
     4. Ewing SK
     5. Le PT
     6. Hue TF
     7. Vittinghoff E
     8. Xu K
     9. Gudnason V
     10. Sigurdsson G
     11. Kado DM
     12. Eiriksdottir G
     13. Harris T
     14. Schafer AL
     15. Li X
     16. Zaidi M
     17. Rosen CJ
     18. Schwartz AV

     (2021) Serum FSH is associated with BMD, bone marrow adiposity, and body composition in the AGES-Reykjavik study of older adults

     The Journal of Clinical Endocrinology and Metabolism 106:e1156–e1169.

     https://doi.org/10.1210/clinem/dgaa922

     • PubMed
     • Google Scholar
205. 1. Vignaux G
     2. Ndong JD
     3. Perrien DS
     4. Elefteriou F

     (2015) Inner ear vestibular signals regulate bone remodeling via the sympathetic nervous system

     Journal of Bone and Mineral Research 30:1103–1111.

     https://doi.org/10.1002/jbmr.2426

     • PubMed
     • Google Scholar
206. 1. Wallner C
     2. Jaurich H
     3. Wagner JM
     4. Becerikli M
     5. Harati K
     6. Dadras M
     7. Lehnhardt M
     8. Behr B

     (2017) Inhibition of GDF8 (myostatin) accelerates bone regeneration in diabetes mellitus type 2

     Scientific Reports 7:9878.

     https://doi.org/10.1038/s41598-017-10404-z

     • PubMed
     • Google Scholar
207. 1. Wan M
     2. Cao X

     (2005) Bmp signaling in skeletal development

     Biochemical and Biophysical Research Communications 328:651–657.

     https://doi.org/10.1016/j.bbrc.2004.11.067

     • PubMed
     • Google Scholar
208. 1. Wang Y
     2. Wan C
     3. Deng L
     4. Liu X
     5. Cao X
     6. Gilbert SR
     7. Bouxsein ML
     8. Faugere M-C
     9. Guldberg RE
     10. Gerstenfeld LC
     11. Haase VH
     12. Johnson RS
     13. Schipani E
     14. Clemens TL

     (2007) The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development

     The Journal of Clinical Investigation 117:1616–1626.

     https://doi.org/10.1172/JCI31581

     • PubMed
     • Google Scholar
209. 1. Wang J
     2. Zhang W
     3. Yu C
     4. Zhang X
     5. Zhang H
     6. Guan Q
     7. Zhao J
     8. Xu J

     (2015) Follicle-Stimulating hormone increases the risk of postmenopausal osteoporosis by stimulating osteoclast differentiation

     PLOS ONE 10:e0134986.

     https://doi.org/10.1371/journal.pone.0134986

     • PubMed
     • Google Scholar
210. 1. Wang CY
     2. Xu Y
     3. Traeger L
     4. Dogan DY
     5. Xiao X
     6. Steinbicker AU
     7. Babitt JL

     (2020) Erythroferrone lowers hepcidin by sequestering BMP2/6 heterodimer from binding to the BMP type I receptor ALK3

     Blood 135:453–456.

     https://doi.org/10.1182/blood.2019002620

     • PubMed
     • Google Scholar
211. 1. Weber JM
     2. Calvi LM

     (2010) Notch signaling and the bone marrow hematopoietic stem cell niche

     Bone 46:281–285.

     https://doi.org/10.1016/j.bone.2009.08.007

     • PubMed
     • Google Scholar
212. 1. Wei J
     2. Ferron M
     3. Clarke CJ
     4. Hannun YA
     5. Jiang H
     6. Blaner WS
     7. Karsenty G

     (2014a) Bone-specific insulin resistance disrupts whole-body glucose homeostasis via decreased osteocalcin activation

     The Journal of Clinical Investigation 124:1–13.

     https://doi.org/10.1172/JCI72323

     • PubMed
     • Google Scholar
213. 1. Wei J
     2. Hanna T
     3. Suda N
     4. Karsenty G
     5. Ducy P

     (2014b) Osteocalcin promotes β-cell proliferation during development and adulthood through GPRC6A

     Diabetes 63:1021–1031.

     https://doi.org/10.2337/db13-0887

     • PubMed
     • Google Scholar
214. 1. Wu X-B
     2. Li Y
     3. Schneider A
     4. Yu W
     5. Rajendren G
     6. Iqbal J
     7. Yamamoto M
     8. Alam M
     9. Brunet LJ
     10. Blair HC
     11. Zaidi M
     12. Abe E

     (2003) Impaired osteoblastic differentiation, reduced bone formation, and severe osteoporosis in noggin-overexpressing mice

     The Journal of Clinical Investigation 112:924–934.

     https://doi.org/10.1172/JCI15543

     • PubMed
     • Google Scholar
215. 1. Wu Y
     2. Torchia J
     3. Yao W
     4. Lane NE
     5. Lanier LL
     6. Nakamura MC
     7. Humphrey MB

     (2007) Bone microenvironment specific roles of ITAM adapter signaling during bone remodeling induced by acute estrogen-deficiency

     PLOS ONE 2:e586.

     https://doi.org/10.1371/journal.pone.0000586

     • PubMed
     • Google Scholar
216. 1. Wu X-Y
     2. Wu X-P
     3. Xie H
     4. Zhang H
     5. Peng Y-Q
     6. Yuan L-Q
     7. Su X
     8. Luo X-H
     9. Liao E-Y

     (2010) Age-Related changes in biochemical markers of bone turnover and gonadotropin levels and their relationship among Chinese adult women

     Osteoporosis International 21:275–285.

     https://doi.org/10.1007/s00198-009-0943-9

     • PubMed
     • Google Scholar
217. 1. Wu C
     2. Rankin EB
     3. Castellini L
     4. Alcudia JF
     5. LaGory EL
     6. Andersen R
     7. Rhodes SD
     8. Wilson TLS
     9. Mohammad KS
     10. Castillo AB
     11. Guise TA
     12. Schipani E
     13. Giaccia AJ

     (2015) Oxygen-Sensing PhDs regulate bone homeostasis through the modulation of osteoprotegerin

     Genes & Development 29:817–831.

     https://doi.org/10.1101/gad.255000.114

     • PubMed
     • Google Scholar
218. 1. Wu M
     2. Chen G
     3. Li YP

     (2016) Tgf-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease

     Bone Research 4:16009.

     https://doi.org/10.1038/boneres.2016.9

     • PubMed
     • Google Scholar
219. 1. Wysolmerski JJ

     (2002) The evolutionary origins of maternal calcium and bone metabolism during lactation

     Journal of Mammary Gland Biology and Neoplasia 7:267–276.

     https://doi.org/10.1023/a:1022800716196

     • PubMed
     • Google Scholar
220. 1. Xiong J.
     2. Onal M
     3. Jilka RL
     4. Weinstein RS
     5. Manolagas SC
     6. O’Brien CA

     (2011) Matrix-embedded cells control osteoclast formation

     Nature Medicine 17:1235–1241.

     https://doi.org/10.1038/nm.2448

     • PubMed
     • Google Scholar
221. 1. Xiong J
     2. Piemontese M
     3. Onal M
     4. Campbell J
     5. Goellner JJ
     6. Dusevich V
     7. Bonewald L
     8. Manolagas SC
     9. O’Brien CA

     (2015) Osteocytes, not osteoblasts or lining cells, are the main source of the RANKL required for osteoclast formation in remodeling bone

     PLOS ONE 10:e0138189.

     https://doi.org/10.1371/journal.pone.0138189

     • PubMed
     • Google Scholar
222. 1. Xu Z-R
     2. Wang A-H
     3. Wu X-P
     4. Zhang H
     5. Sheng Z-F
     6. Wu X-Y
     7. Xie H
     8. Luo X-H
     9. Liao E-Y

     (2009) Relationship of age-related concentrations of serum FSH and LH with bone mineral density, prevalence of osteoporosis in native Chinese women

     Clinica Chimica Acta; International Journal of Clinical Chemistry 400:8–13.

     https://doi.org/10.1016/j.cca.2008.09.027

     • PubMed
     • Google Scholar
223. 1. Yakar S
     2. Liu JL
     3. Stannard B
     4. Butler A
     5. Accili D
     6. Sauer B
     7. LeRoith D

     (1999) Normal growth and development in the absence of hepatic insulin-like growth factor I

     PNAS 96:7324–7329.

     https://doi.org/10.1073/pnas.96.13.7324

     • PubMed
     • Google Scholar
224. 1. Yakar S
     2. Rosen CJ
     3. Bouxsein ML
     4. Sun H
     5. Mejia W
     6. Kawashima Y
     7. Wu Y
     8. Emerton K
     9. Williams V
     10. Jepsen K
     11. Schaffler MB
     12. Majeska RJ
     13. Gavrilova O
     14. Gutierrez M
     15. Hwang D
     16. Pennisi P
     17. Frystyk J
     18. Boisclair Y
     19. Pintar J
     20. Jasper H
     21. Domene H
     22. Cohen P
     23. Clemmons D
     24. LeRoith D

     (2009) Serum complexes of insulin-like growth factor-1 modulate skeletal integrity and carbohydrate metabolism

     FASEB Journal 23:709–719.

     https://doi.org/10.1096/fj.08-118976

     • PubMed
     • Google Scholar
225. 1. Yamashita T
     2. Murakami T
     3. Otani S
     4. Kuwajima M
     5. Shima K

     (1998) Leptin receptor signal transduction: obra and obrb of fa type

     Biochemical and Biophysical Research Communications 246:752–759.

     https://doi.org/10.1006/bbrc.1998.8689

     • PubMed
     • Google Scholar
226. 1. Yan Y
     2. Tang D
     3. Chen M
     4. Huang J
     5. Xie R
     6. Jonason JH
     7. Tan X
     8. Hou W
     9. Reynolds D
     10. Hsu W
     11. Harris SE
     12. Puzas JE
     13. Awad H
     14. O’Keefe RJ
     15. Boyce BF
     16. Chen D

     (2009) Axin2 controls bone remodeling through the beta-catenin-BMP signaling pathway in adult mice

     Journal of Cell Science 122:3566–3578.

     https://doi.org/10.1242/jcs.051904

     • PubMed
     • Google Scholar
227. 1. Yu W
     2. Zhong L
     3. Yao L
     4. Wei Y
     5. Gui T
     6. Li Z
     7. Kim H
     8. Holdreith N
     9. Jiang X
     10. Tong W
     11. Dyment N
     12. Liu XS
     13. Yang S
     14. Choi Y
     15. Ahn J
     16. Qin L

     (2021) Bone marrow adipogenic lineage precursors promote osteoclastogenesis in bone remodeling and pathologic bone loss

     The Journal of Clinical Investigation 131:e140214.

     https://doi.org/10.1172/JCI140214

     • PubMed
     • Google Scholar
228. 1. Yue R
     2. Zhou BO
     3. Shimada IS
     4. Zhao Z
     5. Morrison SJ

     (2016) Leptin receptor promotes adipogenesis and reduces osteogenesis by regulating mesenchymal stromal cells in adult bone marrow

     Cell Stem Cell 18:782–796.

     https://doi.org/10.1016/j.stem.2016.02.015

     • PubMed
     • Google Scholar
229. 1. Yuen T
     2. Stachnik A
     3. Iqbal J
     4. Sgobba M
     5. Gupta Y
     6. Lu P
     7. Colaianni G
     8. Ji Y
     9. Zhu LL
     10. Kim SM
     11. Li J
     12. Liu P
     13. Izadmehr S
     14. Sangodkar J
     15. Bailey J
     16. Latif Y
     17. Mujtaba S
     18. Epstein S
     19. Davies TF
     20. Bian Z
     21. Zallone A
     22. Aggarwal AK
     23. Haider S
     24. New MI
     25. Sun L
     26. Narla G
     27. Zaidi M

     (2014) Bisphosphonates inactivate human egfrs to exert antitumor actions

     PNAS 111:17989–17994.

     https://doi.org/10.1073/pnas.1421410111

     • PubMed
     • Google Scholar
230. 1. Zaidi M
     2. Datta HK
     3. Patchell A
     4. Moonga B
     5. MacIntyre I

     (1989) “ calcium-activated ” intracellular calcium elevation: a novel mechanism of osteoclast regulation

     Biochemical and Biophysical Research Communications 163:1461–1465.

     https://doi.org/10.1016/0006-291x(89)91143-1

     • PubMed
     • Google Scholar
231. 1. Zaidi M
     2. Shankar VS
     3. Towhidul Alam AS
     4. Moonga BS
     5. Pazianas M
     6. Huang CL

     (1992) Evidence that a ryanodine receptor triggers signal transduction in the osteoclast

     Biochemical and Biophysical Research Communications 188:1332–1336.

     https://doi.org/10.1016/0006-291x(92)91377-3

     • PubMed
     • Google Scholar
232. 1. Zaidi M
     2. Shankar VS
     3. Tunwell R
     4. Adebanjo OA
     5. Mackrill J
     6. Pazianas M
     7. O’Connell D
     8. Simon BJ
     9. Rifkin BR
     10. Venkitaraman AR

     (1995) A ryanodine receptor-like molecule expressed in the osteoclast plasma membrane functions in extracellular Ca2+ sensing

     The Journal of Clinical Investigation 96:1582–1590.

     https://doi.org/10.1172/JCI118197

     • PubMed
     • Google Scholar
233. 1. Zaidi M

     (2007) Skeletal remodeling in health and disease

     Nature Medicine 13:791–801.

     https://doi.org/10.1038/nm1593

     • PubMed
     • Google Scholar
234. 1. Zaidi M
     2. Sun L
     3. Robinson LJ
     4. Tourkova IL
     5. Liu L
     6. Wang Y
     7. Zhu LL
     8. Liu X
     9. Li J
     10. Peng Y
     11. Yang G
     12. Shi X
     13. Levine A
     14. Iqbal J
     15. Yaroslavskiy BB
     16. Isales C
     17. Blair HC

     (2010) Acth protects against glucocorticoid-induced osteonecrosis of bone

     PNAS 107:8782–8787.

     https://doi.org/10.1073/pnas.0912176107

     • PubMed
     • Google Scholar
235. 1. Zaidi M
     2. Iqbal J

     (2012) Translational medicine: double protection for weakened bones

     Nature 485:47–48.

     https://doi.org/10.1038/485047a

     • PubMed
     • Google Scholar
236. 1. Zaidi M
     2. Iqbal J

     (2016) Closing the loop on the bone-resorbing osteoclast

     Nature Medicine 22:460–461.

     https://doi.org/10.1038/nm.4104

     • PubMed
     • Google Scholar
237. 1. Zanotti S
     2. Smerdel-Ramoya A
     3. Stadmeyer L
     4. Durant D
     5. Radtke F
     6. Canalis E

     (2008) Notch inhibits osteoblast differentiation and causes osteopenia

     Endocrinology 149:3890–3899.

     https://doi.org/10.1210/en.2008-0140

     • PubMed
     • Google Scholar
238. 1. Zelcer N
     2. Tontonoz P

     (2006) Liver X receptors as integrators of metabolic and inflammatory signaling

     The Journal of Clinical Investigation 116:607–614.

     https://doi.org/10.1172/JCI27883

     • PubMed
     • Google Scholar
239. 1. Zhang J
     2. Niu C
     3. Ye L
     4. Huang H
     5. He X
     6. Tong W-G
     7. Ross J
     8. Haug J
     9. Johnson T
     10. Feng JQ
     11. Harris S
     12. Wiedemann LM
     13. Mishina Y
     14. Li L

     (2003) Identification of the haematopoietic stem cell niche and control of the niche size

     Nature 425:836–841.

     https://doi.org/10.1038/nature02041

     • PubMed
     • Google Scholar
240. 1. Zhang R
     2. Oyajobi BO
     3. Harris SE
     4. Chen D
     5. Tsao C
     6. Deng HW
     7. Zhao M

     (2013) Wnt/Β-Catenin signaling activates bone morphogenetic protein 2 expression in osteoblasts

     Bone 52:145–156.

     https://doi.org/10.1016/j.bone.2012.09.029

     • PubMed
     • Google Scholar
241. 1. Zhang J
     2. Valverde P
     3. Zhu X
     4. Murray D
     5. Wu Y
     6. Yu L
     7. Jiang H
     8. Dard MM
     9. Huang J
     10. Xu Z
     11. Tu Q
     12. Chen J

     (2017) Exercise-induced irisin in bone and systemic irisin administration reveal new regulatory mechanisms of bone metabolism

     Bone Research 5:16056.

     https://doi.org/10.1038/boneres.2016.56

     • PubMed
     • Google Scholar
242. 1. Zhao M
     2. Qiao M
     3. Harris SE
     4. Oyajobi BO
     5. Mundy GR
     6. Chen D

     (2004) Smurf1 inhibits osteoblast differentiation and bone formation in vitro and in vivo

     The Journal of Biological Chemistry 279:12854–12859.

     https://doi.org/10.1074/jbc.M313294200

     • PubMed
     • Google Scholar
243. 1. Zhao C
     2. Irie N
     3. Takada Y
     4. Shimoda K
     5. Miyamoto T
     6. Nishiwaki T
     7. Suda T
     8. Matsuo K

     (2006) Bidirectional ephrinb2-ephb4 signaling controls bone homeostasis

     Cell Metabolism 4:111–121.

     https://doi.org/10.1016/j.cmet.2006.05.012

     • PubMed
     • Google Scholar
244. 1. Zhao B
     2. Takami M
     3. Yamada A
     4. Wang X
     5. Koga T
     6. Hu X
     7. Tamura T
     8. Ozato K
     9. Choi Y
     10. Ivashkiv LB
     11. Takayanagi H
     12. Kamijo R

     (2009) Interferon regulatory factor-8 regulates bone metabolism by suppressing osteoclastogenesis

     Nature Medicine 15:1066–1071.

     https://doi.org/10.1038/nm.2007

     • PubMed
     • Google Scholar
245. 1. Zhou S
     2. Turgeman G
     3. Harris SE
     4. Leitman DC
     5. Komm BS
     6. Bodine PVN
     7. Gazit D

     (2003) Estrogens activate bone morphogenetic protein-2 gene transcription in mouse mesenchymal stem cells

     Molecular Endocrinology 17:56–66.

     https://doi.org/10.1210/me.2002-0210

     • PubMed
     • Google Scholar
246. 1. Zhu H
     2. Kavsak P
     3. Abdollah S
     4. Wrana JL
     5. Thomsen GH

     (1999) A Smad ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation

     Nature 400:687–693.

     https://doi.org/10.1038/23293

     • PubMed
     • Google Scholar
247. 1. Zhu LL
     2. Blair H
     3. Cao J
     4. Yuen T
     5. Latif R
     6. Guo L
     7. Tourkova IL
     8. Li J
     9. Davies TF
     10. Sun L
     11. Bian Z
     12. Rosen C
     13. Zallone A
     14. New MI
     15. Zaidi M

     (2012a) Blocking antibody to the β-subunit of FSH prevents bone loss by inhibiting bone resorption and stimulating bone synthesis

     PNAS 109:14574–14579.

     https://doi.org/10.1073/pnas.1212806109

     • PubMed
     • Google Scholar
248. 1. Zhu LL
     2. Tourkova I
     3. Yuen T
     4. Robinson LJ
     5. Bian Z
     6. Zaidi M
     7. Blair HC

     (2012b) Blocking FSH action attenuates osteoclastogenesis

     Biochemical and Biophysical Research Communications 422:54–58.

     https://doi.org/10.1016/j.bbrc.2012.04.104

     • PubMed
     • Google Scholar
249. 1. Zhu J
     2. Zhang C
     3. Jia J
     4. Wang H
     5. Leng H
     6. Xu Y
     7. Wu C
     8. Zhang Q
     9. Song C

     (2021) Osteogenic effects in a rat osteoporosis model and femur defect model by simvastatin microcrystals

     Annals of the New York Academy of Sciences 1487:31–42.

     https://doi.org/10.1111/nyas.14513

     • PubMed
     • Google Scholar