It is widely accepted that bone and muscle interact mechanically as movement of the skeleton by muscle is essential for life. Less well-known but becoming more generally accepted is that muscle and bone can communicate through secreted factors (Brotto and Bonewald, 2015; Bonewald, 2019). Muscle produces factors such as β-aminoisobutyric acid and irisin with exercise, that have positive effects on bone, adipose tissue, brain, and other organs, whereas sedentary muscle produces factors such as myostatin that has negative effects on both bone and muscle (Brotto and Bonewald, 2015; Karsenty and Mera, 2018; Kitase et al., 2018; Boström et al., 2012; Hamrick et al., 2006).

Many of the factors secreted by bone are produced by osteocytes, the most abundant and the longest-living bone cell (Bonewald, 2011; Dallas et al., 2013). These cells are derived from terminally differentiated osteoblasts that become surrounded by the newly mineralizing bone matrix (Dallas et al., 2013). Osteocytes are multifunctional and appear to be the major mechanosensory cell in bone (Bonewald, 2011; Temiyasathit and Jacobs, 2010; Uda et al., 2017). Under unloaded conditions, these cells produce sclerostin, a negative regulator of bone formation and receptor activator of nuclear factor kappa β ligand (RANKL), the major factor that recruits and activates osteoclasts to resorb bone (Nakashima et al., 2011; Xiong and O’Brien, 2012; Xiong et al., 2015; Ono et al., 2020). In contrast, with anabolic mechanical loading, these cells produce factors such as prostaglandin E2 that have positive effects on myogenesis and muscle function (Mo et al., 2015). Osteocytes play a major role in mineral metabolism, through regulation of both calcium and phosphate homeostasis. Osteocytes secrete fibroblast growth factor 23 to target the kidney to regulate phosphate excretion. Both parathyroid hormone (PTH) and parathyroid-related peptide (PTHrP) regulate calcium homeostasis via the PTH type 1 receptor on osteocytes (Feng et al., 2009; Teti and Zallone, 2009). Under the physiological calcium-demanding condition of lactation, osteocytes respond to PTHrP by removing their surrounding perilacunar matrix to provide calcium for offspring, and upon weaning this perilacunar matrix is rapidly replaced, a process referred to as perilacunar remodeling (Qing and Bonewald, 2009; Qing et al., 2012; Wysolmerski, 2013). However, under pathological conditions such as ovariectomy, hyperparathyroidism, hypophosphatemic rickets, and cancer, excessive removal of their perilacunar matrix occurs through osteocytic osteolysis (Tsourdi et al., 2018; Jähn-Rickert and Zimmermann, 2021; Pin et al., 2021; Shimonty et al., 2023).

Bone is the largest calcium reservoir in the body and human mothers can lose an average of 250 mg/day of calcium in milk, emphasizing the need for a calcium-replete diet to prevent bone loss (Qing et al., 2012; Wysolmerski, 2002; Kalkwarf, 2004). During lactation, PTHrP targets the osteocyte to elevate genes coding for factors necessary for the removal of their calcium-ladened perilacunar matrix and to increase RANKL as an activator of osteoclasts (Kovacs, 2001). During lactation, RANKL targets osteoclasts, thereby driving osteoclastic bone resorption. Osteocytic osteolysis is accomplished through the expression of ‘osteoclast-specific’ genes such as cathepsin K (Ctsk), tartrate-resistant acid phosphatase (TRAP, gene Acp5), and carbonic anhydrase 1 (Car 1) (Qing and Bonewald, 2009; Qing et al., 2012). In addition, there is an increase in genes coding for the proton pumps, ATPase H⁺ transporting V1 subunit G1 (Atp6v1g1), and ATPase H⁺ transporting V0 subunit D2 (Atp6v0d2) necessary to dissolve and remove calcium from bone collagen (Jähn et al., 2017).

Systemic calcium deficiency such as a decrease in dietary calcium triggers an increase in PTH, acting to mobilize calcium from bones to maintain normal homeostatic circulating calcium (Goltzman, 2008). Worldwide, over 3.5 billion people suffer from dietary calcium deficiency, and women are at a higher risk of this condition (Kumssa et al., 2015; Body et al., 2016). Aging often results in hypocalcemia and bone loss due to low vitamin D, hypoparathyroidism, genetic abnormalities, medications decreasing dietary calcium absorption, and menopause in women. Calcium deficiency can lead to osteopenia, osteoporosis, and increased fracture risk, primarily due to secondary hyperparathyroidism (Kumssa et al., 2015; Body et al., 2016).

Irisin is a recently discovered myokine generated in response to exercise when fibronectin type III domain containing protein 5 (FNDC5) is proteolytically cleaved by a yet undetermined protease (Boström et al., 2012). FNDC5 is expressed in the heart, kidney, testes, brain, and other tissues; however, skeletal muscle appears to be the primary producer (Erickson, 2013; Maak et al., 2021; Tsourdi et al., 2022). Cleaved irisin circulates to distant organs, such as adipose tissue where irisin increases a thermogenic gene program, including the expression of uncoupling protein 1 in a process referred to as browning. This is associated with increased energy expenditure and improvement in glucose tolerance, both of which are important for the prevention of type 2 diabetes and the reduction of complications from obesity (Perakakis et al., 2017; Korta et al., 2019). Irisin can also regulate glucose uptake in skeletal muscle (Lee et al., 2015), and increases myogenesis and oxidative metabolism, responsible for increasing skeletal muscle mass (Colaianni and Grano, 2015). Irisin also plays an important positive role in cognitive functions with exercise, aging, and degenerative diseases such as Alzheimer’s disease and Parkinson’s disease (Islam et al., 2021). Using the tail-vein injection method to deliver exogenous irisin, it was shown that irisin can cross the blood-brain barrier (Islam et al., 2021).

Results from studies regarding the effects of irisin on the skeleton are complex and somewhat contradictory. Colaianni et al., 2015 have shown that recombinant irisin exerts a beneficial effect on cortical bone in young male mice by reducing the secretion of osteoblast inhibitors and increasing the activity of osteogenic cells. However, another study has shown that recombinant irisin treatment of MLO-Y4 osteocyte-like cells induces gene- and protein-level expression of Sost/sclerostin, a negative regulator of bone formation while maintaining cell viability under oxidative stress (Kim et al., 2018). Estell et al., 2020 have shown using female FNDC5 overexpressing female mice that irisin acts directly on osteoclast progenitors to increase differentiation and promote bone resorption. Kim et al., 2018 have shown that 9-month-old ovariectomized FNDC5 global knockout (KO) mice are protected against ovariectomy-induced trabecular bone loss through the inactivation of osteocytic osteolysis and osteoclastic bone resorption. The majority of these studies used only male or female mice, suggesting a sex-dependent response may be responsible for these seemingly opposing findings (Estell et al., 2020; Colaianni et al., 2017; Kawao et al., 2018; Ma et al., 2018; Colucci et al., 2021; Posa et al., 2021).

As shown previously, FNDC5 deletion has a protective effect against ovariectomy- induced bone loss via a reduction of osteocytic osteolysis and osteoclastic resorption (Kim et al., 2018). We, therefore, hypothesized that FNDC5 deletion would also be protective against bone loss due to calcium deficiency that occurs with lactation and a calcium-deficient diet. Our data show that the female skeleton in FNDC5 null female mice was resistant to bone loss due to both lactation and low calcium. However, for FNDC5 null males, deletion not only failed to protect but exacerbated bone loss in response to low calcium. We propose that male and female osteocytes respond to irisin differently under calcium-demanding conditions based on the divergence of the male and female osteocyte transcriptome with sexual maturity when the female osteocyte must serve a critical role in reproduction and lactation.

Irisin has been shown to be increased in the blood of humans and mice with exercise. Irisin, working mainly through its receptor αVβ5 integrin, has been shown to have powerful effects on fat, bone, and brain tissues (Boström et al., 2012; Tsourdi et al., 2022; Korta et al., 2019; Islam et al., 2021; Kim et al., 2018; Colaianni et al., 2017; Wrann et al., 2013; Xin et al., 2016; Wang et al., 2017; Bao et al., 2022; Zhang et al., 2022). With regard to bone, studies have generated complex and even contradictory results (Erickson, 2013; Maak et al., 2021; Colaianni and Grano, 2015; Kim et al., 2018; Estell et al., 2020; Colaianni et al., 2014; Zhang et al., 2018). Of note, the majority of bone studies have been performed either exclusively on males, or females, but few on both. Most studies have used recombinant irisin treatment whereas we have focused on the effects of deleting irisin. Other studies have mainly examined the effects on osteoblasts and osteoclasts, whereas our studies have focused on osteocytes (Kim et al., 2018).

Global deletion of FNDC5 on a normal diet had essentially no effect on bone in females, but in contrast, the null male mice have significantly more bone compared to WT males, but this bone has impaired mechanical properties. This suggests that the lack of FNDC5 is having no effect on the development or growth of the female skeleton, but does affect the male skeleton, increasing the size yet impairing matrix properties responsible for strength. Examination of their osteocytes showed that both female and male null mice have significantly fewer TRAP-positive osteocytes compared to their sex-matched WT controls suggesting that their osteocytes are more quiescent or less primed for bone resorption.

Challenging the null animals with calcium deficiency revealed dramatic differences in osteocytic osteolysis and osteoclast activation, two major functions of osteocytes. Deletion of FNDC5 in females is partially protective against calcium deficiency, but deletion in males accelerates both of these osteocyte functions resulting in greater bone loss compared to controls. We have shown previously that under calcium-demanding conditions such as lactation, osteocytes express genes previously thought only to be specific for osteoclasts including cathepsin K, TRAP, carbonic anhydrase, the proton pump V-ATPase, and others (Qing et al., 2012) and shown that osteocytes are the major source of RANKL (Nakashima et al., 2011; Xiong and O’Brien, 2012; Xiong et al., 2015). In this study, lactating females lacking FNDC5 were partially resistant to bone loss, similar to ovariectomized females as previously published (Kim et al., 2018). To determine the effects of calcium deficiency on males, mice were given a low-calcium diet for 2 weeks. Unlike the protective effects of FNDC5/irisin deletion in females, bone loss was exacerbated in null males compared to controls on a low-calcium diet.

With 2 weeks of lactation and litter size comparable to WT controls, the null female mice had less circulating RANKL, fewer TRAP-positive osteoclasts, fewer TRAP-positive osteocytes, and smaller lacunar size. Our observation that the deletion of FNDC5/irisin makes lactating mice partially resistant to bone loss has an important implication with regard to the purpose of lactation. Lactation is a critical period for pups as they obtain essential nutrients, especially calcium, from the mother’s milk for their proper growth. Calcium lost by the mother’s bone during lactation is rapidly replaced upon weaning with complete recovery of bone mass within a week (Qing et al., 2012; Wysolmerski, 2002; Kalkwarf, 2004; Kovacs, 2001; Wysolmerski, 2012). Our data suggest that FNDC5/irisin acts as a regulator of calcium release from maternal bones to fulfill the offspring demands during lactation. Therefore, irisin appears to play a beneficial role in ensuring offspring survival and consequently, successful reproduction.

To determine if low calcium would have a similar effect on male FNDC5 null bone, both males and females were subjected to a low-calcium diet for 2 weeks. The effects of a low-calcium diet on female osteocytes and bone loss were essentially identical to the effects of lactation, with two exceptions. First, serum RANKL levels were not significantly different between virgin and lactating null females, while they were between null females on a normal compared to a calcium diet suggesting that RANKL plays less of a role in lactation compared to calcium deficiency. Second, the medullary cavity and endosteal bone in the low-calcium females were completely protected in the FNDC5 null females but were not in the lactating FNDC5 null mice. Bone loss due to lactation or due to dietary calcium deficiency may target different bone sites. Our unpublished observations suggest that endosteal bone is removed faster than periosteal bone with lactation, but this remains to be carefully validated. This difference may also be due to elevated PTHrP during lactation (Kovacs, 2001), whereas hypocalcemia increases circulating PTH levels (Goltzman, 2008), and it is not clear if hormones target distinct bone sites. Similar to the lactating FNDC5 null mice, the null females placed on the low-calcium diet had fewer TRAP-positive osteoclasts, fewer TRAP-positive osteocytes, and smaller lacunar size. Serum RANKL levels increased in both WT and null mice with dietary calcium deficiency, therefore, serum RANKL alone is not enough to explain the partial protective effect of FNDC5 deletion against bone loss. In summary, female null mice are not only resistant to bone loss due to estrogen deficiency as we showed previously (Kim et al., 2018) but are also resistant to calcium deficiency either due to an increase in PTHrP as with lactation, or an increase in PTH as with a low-calcium diet.

Osteoporosis manifests earlier in females due to menopause, but males also develop osteoporosis but at an older age (Johannesdottir et al., 2013; Johnston and Dagar, 2020), and the elderly are known to suffer from calcium deficiency which accelerates bone loss (Kumssa et al., 2015; Body et al., 2016). Dietary calcium deficiency has been shown previously to affect female and male bone differently where female rat bones are more sensitive to a low-calcium diet compared to males (Geng and Wright, 2001). Similarly, in our study, we saw that WT females were more affected by calcium deficiency and lost more bone compared to WT male mice. However, the opposite was observed for the FNDC5/irisin null mice, where female null mice were partially resistant, and male null mice were more susceptible to bone loss with calcium deficiency compared to their WT counterparts. Despite starting with more bone volume compared to WT, the FNDC5 null males had increased osteocyte lacunar area and lost more bone with dietary calcium deficiency compared to WT males. This greater bone loss can be explained through the dramatic increase of TRAP-positive osteocytes and TRAP-positive osteoclasts, but not by a significantly greater increase in circulating RANKL. This sex difference indicates that FNDC5/irisin may be involved in the regulation of calcium release from bone via osteocytes in a sex-dependent manner.

Lacunar area is an indicator of osteocyte regulation of their lacunar microenvironment. Here, we report that osteocyte lacunar size is significantly larger in virgin WT female mice compared to same-age WT males. This difference in lacunar area indicates a distinction between female and male osteocyte function. The mammalian skeleton is a sexually dimorphic organ (Sharma et al., 2023), and female and male bones respond differently to circulating factors, hormones, and myokines as well as other challenges (Kurapaty and Hsu, 2022; Lu et al., 2022; Osipov et al., 2022). As osteocytes are regulators of bone formation and resorption (Bonewald, 2011; Dallas et al., 2013; Robling and Bonewald, 2020), this sex difference may be due to differences in male and female osteocytes. A recent study by Youlten and colleagues has shown that male and female osteocyte transcriptomes are distinctly different (Youlten et al., 2021). At 4 weeks of age, the female osteocyte transcriptome diverges from the male osteocyte transcriptome and these differences continue with age. A cluster of genes more highly expressed in female osteocytes compared to male osteocytes are those involved in bone resorption, the same ones elevated in osteocytes in response to lactation. These transcripts include genes necessary for osteocytic perilacunar remodeling and reduction in pH, which are essential for calcium removal (Qing et al., 2012). This suggests that the larger lacunar area in female osteocytes compared to male osteocytes may be due to the higher expression of bone resorption genes.

The magnitude of the effect size due to FNDC5 deficiency appears modest with regard to the quantitative cortical bone parameters. However, if one examines the changes in osteocyte lacunar size and the mechanical properties of these bones, the differences are greater. As shown in Figure 3E, the lacunar area of the WT females on a low-calcium diet increases by over 30% and the FNDC5 null by less than 20%, while in the males it is approximately 38% in WT compared to 46% in null. According to Buenzli and Sims, 2015, a potential total loss of ~16,000 mm³ (16 mL) of bone occurs through lactation in the human skeleton. This was based on our measurements in lactation-induced murine osteocytic osteolysis (Qing et al., 2012). They used our 2D section of tibiae from lactating mice showing an increase in lacunar size from 38 to 46 µm². In that paper we also showed that canalicular width is increased with lactation. Therefore, this suggests dramatically lower intracortical porosity due to the osteocyte lacunocanalicular system in female null mice compared to female WT mice either with lactation or a low-calcium diet and a dramatic increase in intracortical porosity in null males compared to WT males on a low-calcium diet. Based on these data, using the FNDC5 null animals, we would speculate that the product of FNDC5, irisin, is having a significant effect on the ultrastructure of bone in both males and females challenged with a low-calcium diet.

To begin to understand the molecular mechanisms responsible for the sex and genotype differences, we compared the osteocyte transcriptomes of 5-month-old female and male, WT and null mice. Our results show that the osteocyte transcriptomes of female and male WT mice are significantly different under normal conditions. A surprising difference we observed but not described in the Youlten paper (Youlten et al., 2021) was that compared to WT female osteocytes, WT male osteocytes have much higher expression of genes involved in steroid, lipid, and cholesterol metabolism and transport pathways, lipid and solute carrier genes, and apolipoprotein genes. This suggests that osteocyte metabolism and bioenergetics are distinctly different between WT females and WT males. We hypothesize that the DEGs in these bioenergetic and metabolic pathways modulate bone mass and formation and may shed light on the sexual dimorphism of bones. As these differentially regulated pathways were not previously reported by Youlten et al., 2021, this may be due to differences in strain, housing, diet, or microbiome. Another explanation is the greater osteocyte purity in our study as we used a series of collagenase digestions and EDTA chelation to remove any surface cells which was not performed in the Youlten paper (Youlten et al., 2021).

A second major difference between female and male WT osteocytes was the higher expression of genes involved in collagen matrix formation, bone mineralization, remodeling, resorption, and osteocytic osteolysis pathways in females compared to males. Many of the highly expressed bone resorption genes in WT female osteocytes have been shown to be elevated during lactation (Qing et al., 2012) including Acp5, Ctsk, and Mmp13, all involved in osteocytic osteolysis. This further supports our hypothesis that WT female osteocytes are more primed for resorption compared to WT males, presumably to meet the increased calcium demand during lactation, and correlates with the observed larger lacunae compared to males.

TGFβ is another potential player in osteocyte perilacunar/canalicular remodeling. Alliston and colleagues generated transgenic mice with reduced expression of the TGFβ type II receptor in mice expressing Dmp1-Cre (Dole et al., 2020) (PMID: 32282961) and found a significant difference in bone parameters and markers of osteocyte perilacunar remodeling between the sexes. The females were subjected to lactation and the transgenics were found to be resistant to osteocytic osteolysis compared to controls. However, these investigators did not investigate the lacunar remodeling process in males as compared to females as was performed in the present study using a low-calcium diet. Their study does suggest that TGFβ is involved in the osteocytic osteolysis that occurs with lactation, however, even though the transgenic males showed a disrupted lacunocanlicular network compared to WT males, this does not necessarily indicate a defect in perilacunar remodeling. It is more likely that the defect occurred during bone formation when osteoblasts were differentiating into osteocytes. In our study, we observed a higher expression of TGFb3 in WT female mice compared to WT male mice, with no significant differences in TGFb1 or TGFb2 expression. This suggests that TGFβ3 may play a role in generating the larger lacunar area in WT females compared to WT males through increased matrix-related signaling in irisin-replete conditions.

Few differences were observed between WT female and null female osteocyte transcriptomes as would be expected for bone morphometry and the only difference observed was the number of TRAP-positive osteocytes. In contrast, osteocytes from WT males and null males are significantly different with regard to fatty acid and lipid metabolism pathways whereas null male mice have lower expression of these genes compared to WT males. This suggests a role for irisin in lipid metabolism and bioenergetics in male osteocytes. Lower expression in the null male mice may be responsible for the higher bone mass and inferior biomechanical properties compared to WT males suggesting these pathways mediate the effects of FNDC5/irisin on male bone.

Osteocytes from null females have higher expression of genes and pathways involved in collagen matrix organization, ossification, and mineralization compared to null males. Unlike WT males and females, there was no difference in expression of lipid, cholesterol, and fatty acid metabolism genes in null males compared to null females. Again, this indicates that FNDC5/irisin regulates male bone through these lipid-related pathways.

Lactation and calcium deficiency induce the same changes in females. Similar to that reported previously for lactation (Qing et al., 2012), osteocytes from WT female mice on a low-calcium diet exhibited an increase of several osteoclast/resorption/lactation genes including Acp5, Ctsk, Oscar, Mst1r, and Pth1r compared to WT females on a normal diet. Surprisingly, we also observed an increase in bone formation genes including Col1a1, Alpl, and Bglap. As osteocytic osteolysis is rapidly reversed within a week of weaning, the osteocyte may be preparing to rapidly reverse bone loss. We propose that once calcium is replenished, shutting off the proton pump will rapidly reverse the pH within the osteocyte lacunae, allowing bone-forming proteins such as alkaline phosphatase to become active to rapidly replace the osteocyte perilacunar matrix (Jähn et al., 2017; Andersson et al., 2003; Silver et al., 1988; Kaplan, 1972; Farley and Baylink, 1986).

The main molecular mechanism responsible for the resistance of null female mice to calcium deficiency compared to WT female mice is lower expression of genes such as Tnfsf11, responsible for osteoclastic resorption. A correspondingly lower expression of bone formation genes including Col1a1, Alpl, and Bglap compared to WT females on a low-calcium diet was observed. The lower expression of both formation and resorption genes suggests a coupling of resorption with formation. Irisin appears to regulate calcium release in the female skeleton.

Osteocytes from WT male mice on a low-calcium diet expressed higher levels of bone resorption genes including Tnsfs11, Acp5, Ctsk, Oscar, and Mst1r compared to WT male mice on a normal diet as expected. Like the females, there is a coupling with bone formation genes as there is also an increase in Bglap and Col1a1, suggesting the potential for osteocytes to rapidly replace their perilacunar matrix with calcium repletion. Similarly, the male null mice with calcium deficiency showed an increase in bone resorption genes including Tnsfs11, Oscar, and Car3, as well as an increase in bone formation genes such as Alpl and Bglap compared to null mice on a normal diet. The major differences between WT male mice with calcium deficiency and FNDC5 null male mice with calcium deficiency were the lower expression of genes involved in the extracellular matrix organization, ossification, and bone development pathways in the null male mice compared to WT males. This suggests a mechanism for how null male mice lose more bone with calcium deficiency compared to WT males.

Irisin could be having direct or indirect effects on osteocytes. Irisin can modulate adipose tissue (Boström et al., 2012; Zhang et al., 2014; Celi and Brown, 2017; Luo et al., 2022), can potentially modulate osteogenic differentiation of bone marrow mesenchymal stem cells through αVβ5 (Zhu et al., 2023), and bone marrow adipose tissue can modulate bone properties (Yeung et al., 2005; Rosen and Bouxsein, 2006; Muruganandan and Sinal, 2014; Styner et al., 2015; Schwartz, 2015; During, 2020) as well as osteocyte number and activity (Al Saedi et al., 2019; Al Saedi et al., 2020). Irisin can modulate brain activity and signaling (Islam et al., 2021; Wrann et al., 2013; Young et al., 2019; Jo and Song, 2021; Qi et al., 2022) through BDNF (Wrann et al., 2013) and BDNF promotes osteogenesis in human bone mesenchymal stem cells (Liu et al., 2018). Our data do not show significant expression of Fndc5 in osteocytes. Studies from our group have found no expression of Fndc5 in primary osteoblasts and primary osteocytes (transcriptome analysis with a raw count of 8–12), however both skeletal muscle (gastrocnemius) and C2C12 myotubes have high expression of Fndc5 (transcriptome raw count of 512–1000, unpublished). As such, we postulate that the effect of irisin on osteocytes is not an autocrine effect, but rather due to irisin production by skeletal muscle.

Irisin must bind to αVβ5 integrins to function. Osteocytes express high levels of this receptor which was first discovered using the female MLO-Y4 osteocyte-like cell line (Kim et al., 2018). Integrins are usually stable in the cell membrane with a half-life of 12–24 hr (Moreno-Layseca et al., 2019). In our RNA sequencing data, we observed a stable expression of both ITGAV and ITGB5, encoding integrins αV and β5 respectively, with no differences between either WT or null, male or female, calcium-replete or calcium-deficient mice. Recently it has been published that Hsp90α is necessary to facilitate irisin-αVβ5 binding (Mu et al., 2023). Hsp90a, the gene encoding this heat shock protein, is very highly expressed in both WT and null male and female mice, with no significant regulation by diet. The high expression of Hsp90α in osteocytes may explain their significant and rapid responses to irisin (Kim et al., 2018).

In summary, during normal development and on a regular diet, FNDC5/irisin deletion has few if any effects on the female skeleton but a significant effect on the male skeleton resulting in more but weaker bone. However, with challenges, such as calcium deficiency, dramatic differences were observed. Our data suggest that irisin activates the osteocyte in females to initiate the removal of their perilacunar matrix and for bone resorption through osteoclast activation, presumably to provide calcium for reproduction purposes. In contrast, in males, irisin protects against osteocytic osteolysis and osteoclastic bone resorption under calcium-demanding conditions. This sex-specific effect may be due to the sexual dimorphism of the osteocyte transcriptome. The major findings of our work is summarized in (Figure 8). We have discovered a new novel function of irisin to ensure the survival of offspring and that irisin is essential for male but not female skeletal development. These findings could have implications for understanding sex-dependent differences in bone diseases, such as osteoporosis, and lead to the development of sex-targeted therapies.

Figure 8

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The osteocyte transcriptome sequencing data have been deposited in GEO under accession number GSE242445.

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Author details

1. Anika Shimonty

   Indiana University, Indianapolis, United States

   Contribution

   Data curation, Formal analysis, Investigation, Writing - original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0009-0005-2954-2991

2. Fabrizio Pin

   Indiana University, Indianapolis, United States

   Contribution

   Data curation, Formal analysis, Writing – review and editing

   Competing interests

   No competing interests declared

3. Matthew Prideaux

   Indiana University, Indianapolis, United States

   Contribution

   Data curation, Formal analysis, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9211-9698

4. Gang Peng

   Indiana University, Indianapolis, United States

   Contribution

   Data curation, Formal analysis, Visualization, Writing – review and editing

   Competing interests

   No competing interests declared

5. Joshua Huot

   Indiana University, Indianapolis, United States

   Contribution

   Data curation, Formal analysis, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

6. Hyeonwoo Kim

   Korea Advanced Institute of Science and Technology, Daejon, Republic of Korea

   Contribution

   Conceptualization, Resources, Writing – review and editing

   Competing interests

   No competing interests declared

7. Clifford J Rosen

   Maine Health Access Foundation, Portland, United States

   Contribution

   Conceptualization, Project administration, Writing – review and editing

   Competing interests

   No competing interests declared

8. Bruce M Spiegelman

   Dana Farber Cancer Institute, Boston, United States

   Contribution

   Conceptualization, Resources, Project administration, Writing – review and editing

   Competing interests

   No competing interests declared

9. Lynda F Bonewald

   1. Indiana University, Indianapolis, United States
   2. Indiana Center for Musculoskeletal Health, Indianapolis, United States

   Contribution

   Conceptualization, Resources, Supervision, Writing - original draft, Project administration, Writing – review and editing

   For correspondence

   lbonewal@iu.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5536-9943

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