Our bones are living tissues which constantly reshape and renew themselves. This ability relies on stem cells present in the marrow cavity, which can mature into the various types of cells needed to produce new bone material, marrow fat, or other components.

Obesity and associated conditions such as type 2 diabetes are often linked to harmful changes in the skeleton. In particular, these metabolic conditions are associated with weight-bearing bones becoming more prone to facture and healing poorly. Mice genetically modified to model obesity and diabetes could help researchers to study exactly how these conditions – and the genetic changes that underlie them – impact bone health.

Gomez et al. aimed to address this question by focusing on KSR2, a gene involved in energy consumption and feeding behavior. Children who carry certain KSR2 mutations are prone to obesity and type 2 diabetes; mice lacking the gene also develop these conditions due to uncontrolled eating.

Closely examining mutant mice in which Ksr2 had been deactivated in every cell revealed that the weight-bearing bones of these animals were also more likely to break, and the fractures then healed more slowly. This was the case even though these bones had higher mass and less marrow fat compared to healthy mice. Non-weight bearing bones (such as the spine) did not exhibit these changes.

Further experiments revealed that, when expressed normally in the skeleton, Ksr2 skews the stem cell maturation process towards marrow fat cells instead of bone-creating cells. This suggests a new role for Ksr2, which therefore seems to independently regulate both feeding behavior and bone health. In addition, the work by Gomez et al. demonstrate that Ksr2 mutant mice could be a useful model to better understand how obesity and diabetes affect human bones, and to potentially develop new therapies.

Obesity is a major public health problem in the United States, afflicting nearly 40% of adults, and has become a prevalent and destructive health disorder linked to some of the major metabolic diseases, including cardiovascular diseases, type 2 diabetes (T2D), and cancer (Devlin and Rosen, 2015; Pagnotti et al., 2019; Shanbhogue et al., 2016; Walsh and Vilaca, 2017). Although obesity may be considered beneficial to bone health, since increased body weight is associated with higher bone mineral density (BMD), the relationship between excess body fat and bone health is complex, given that obesity has been identified as a risk factor for certain fractures (Greco et al., 2015; Ma et al., 2018; Veldhuis-Vlug and Rosen, 2018). The increasing prevalence of obesity and T2D dictates the need for appropriate in vivo animal models to study the mechanisms of action of obesity and T2D on bone metabolism.

The effect of obesity and T2D on bone is an active area of investigation. Studies with several animal models and approaches have contributed to our current understanding of this relationship. Mouse models, in particular, have provided invaluable information through controlled genetic, biochemical, cellular, and molecular approaches to understand the pathological relationship between excess body fat and bone fragility. Most diet-induced obesity studies have reported reduced BMD and trabecular bone mass (Bonnet et al., 2014; Doucette et al., 2015; Inzana et al., 2013; Scheller et al., 2016). By contrast, monogenetic models of obesity have provided a broader range of bone phenotypes, including no change, loss, or gain in bone mass or BMD (Ahn et al., 2006; Baldock et al., 2007; Braun et al., 2012; Steppan et al., 2000; Wang et al., 2007a). There are several explanations for the diversity in skeletal phenotypes in these models, including differences in expression of targeted genes in other tissues besides bone, as well as varied effects of endocrine factors produced in other affected tissues such as the brain, fat, and skeletal muscle. Nevertheless, monogenetic studies have informed the molecular underpinnings of feeding regulation at the hypothalamus, which has fortuitously led to the development of pharmaceuticals to treat a particular population of individuals genetically predisposed to diabetes (Yeo et al., 2021). Although the RANKL monoclonal antibody, denosumab, has been used to treat bone disorders in osteoporotic T2D patients with reduced BMD (Abe et al., 2019), whether these agents can also benefit the population with gains in BMD, which are paradoxically also fragile (Burghardt et al., 2010; Ma et al., 2012), remains to be investigated. Also, it is worthwhile to further identify/study animal models with genetic mutations that phenocopy the human condition to study these interventions. The advent of the genomic era has expanded the list of individual genes associated with obesity and T2D (Loos and Yeo, 2022), yet their effects on bone remain vastly understudied.

Recently, the scaffold proteins kinase suppressor of ras (KSR1 and KSR2) were identified as mediators of energy consumption, utilization, and adipogenic regulation (Brommage et al., 2008; Costanzo-Garvey et al., 2009; Kortum et al., 2005; Pearce et al., 2013; Revelli et al., 2011). Although these two genes function as paralogs, we previously found that only Ksr2 knockout (KO) mice become obese and diabetic (Brommage et al., 2008; Costanzo-Garvey et al., 2009; Kortum et al., 2005; Pearce et al., 2013; Revelli et al., 2011), suggesting that these paralogs have non-redundant roles, although Ksr1 does have a role in adipogenesis (Kortum et al., 2005). Several mutations at the KSR2 loci in humans have been associated with severe early-onset obesity (Pearce et al., 2013), and studies in Ksr2 KO mice have revealed a centrally regulated mechanism by Ksr2 expression and function in the hypothalamus that results in hyperphagia, changes in metabolic rate, and consequently, obesity and T2D (Costanzo-Garvey et al., 2009; Guo et al., 2017; Henry et al., 2014; Pearce et al., 2013; Revelli et al., 2011). Although there are hundreds of mouse genes reported to lead to obesity when disrupted, Ksr2 gene deletion is associated with a profound obese phenotype and lethality at a young age (Brommage et al., 2008; Revelli et al., 2011). In this study, we set out to investigate whether the deletion of Ksr2, an obesity and T2D gene, bears any effect on bone health, and if so, to evaluate the mechanisms by which KSR2 affects bone metabolism. Our studies show that loss of KSR2 function increases long bone trabecular bone mass while reducing marrow adiposity and that KSR2 acts as a molecular switch that controls the differentiation of bone resident mesenchymal stem cells into osteoblast or adipocyte differentiation via an mTOR-dependent mechanism.

The impact of obesity on bone health is an area of significant concern. While obesity is known to exert complex effects on bone mass and skeletal fragility, the mechanisms by which obesity influences bone metabolism are not well understood. In this study, we used a Ksr2 KO genetic mouse model to investigate the relationship between obesity and bone health. We found that the distal femoral metaphyseal trabecular bone was considerably denser in Ksr2 KO compared to littermate WT controls in two genetic backgrounds, while deletion of Ksr1 did not affect trabecular bone mass. At the cellular level, we found by histomorphometric analysis, ex vivo, and in vitro studies via Ksr2 gain and loss of function that KSR2 is a negative regulator of trabecular bone formation that may act by controlling differentiation of mesenchymal stem cells to the osteoblast or adipocyte fate. By contrast, KSR2 did not significantly affect osteoclast formation or functions. Moreover, our data from Ksr2 KO mice that were pair-fed similar to WT mice and osteoblast-specific Ksr2 cKO mice revealed that Ksr2 controls osteoblast differentiation autonomously. At the molecular level, our findings demonstrate that Ksr2 negatively regulates osteoblast differentiation by repressing mTOR activity (Figure 8I). Since global Ksr2 KO mice exhibited delayed fracture healing with an arrest at endochondral ossification, as observed in obese humans with T2D, and since KSR2 genetic polymorphisms are linked to obesity, an understanding of the cellular and molecular pathways of KSR2 regulation of mesenchymal stem cell fate may have important ramifications in promoting bone health in obese individuals.

Genetic differences between mouse strains are known to affect their susceptibility to gain excess weight, with the C57BL/6J strain being more vulnerable, and therefore used more often than DBA/1LacJ to study diet-induced weight gain (Garofalo et al., 2003; Linder, 2006). Also, the impact of genetic background on gene deletion phenotypes is well established (Doetschman, 2009; Linder, 2006). In accord, we noticed that Ksr2 KO mice in the DBA background lived longer than those in the C57 background (data not shown). Since Ksr2 deletion results in weight gain and increased femoral bone mass in both strains, it is highly likely that Ksr2 also regulates bone formation in other genetic backgrounds. This warrants further investigation in other mammals and, in particular, humans. Furthermore, our data show that disruption of the Ksr2 gene had no significant effect on trabecular bone mass in the vertebrae. These data are consistent with what is known in the literature that the heritability of BMD varies across skeletal sites (Kemp et al., 2014; Rowe et al., 2018) and differences in mechanisms that regulate bone accretion in long bones versus vertebrae.

Other monogenetic models that lead to obesity/T2D defects have also investigated bone phenotypes. In particular, knockouts of different genes in the leptin-melanocortin feedback loop that signals satiety in the hypothalamus generally result in obesity, but although the neural circuits are unidirectional, both anabolic and catabolic effects have been observed in bone. For instance, while leptin KO mice result in reduced femur length and BMD (Steppan et al., 2000; Wang et al., 2007a), they have increased vertebral bone mass (Ducy et al., 2000), consistent with the idea that genes can have distinct effects in different anatomical regions. By contrast, Mc4r and Npy1r knockouts result in increased femoral BMD (Ahn et al., 2006; Baldock et al., 2007; Braun et al., 2012), while Mc3r knockouts have reduced femur length and BMD (Lee et al., 2016). Many of these genes, such as Npy1R and Mc4r, are expressed in both hypothalamic neurons and osteoblasts (Baldock et al., 2007; Zhong et al., 2005), which may be partly responsible for the complex skeletal phenotypes seen in these mice. Similarly, Ksr2 is expressed in the hypothalamus, and in this study, we found that it is also expressed and functional in cells of the osteoblastic lineage. Although our pair-feeding and conditional knockout studies define a role for KSR2 function in bone that can be dissociated from its hypothalamic function, Ksr2 global knockout and likely humans with KSR2 genetic polymorphisms have malfunctions of both hypothalamic KSR2 regulated food intake as well as bone KSR2 regulated osteoblast formation. In future studies, we will address whether Ksr2 plays similar or different roles in other skeletal sites and whether conditional hypothalamic deletion of Ksr2 has any effect on bone physiology.

An alternative means to study the effect of obesity on bone is provided by diet-induced obesity models. Generally, these mice result in excess body fat, with reduced trabecular bone mass at the expense of increased MAT (Bonnet et al., 2014; Scheller et al., 2016; Tencerova et al., 2018). This would suggest excess body adipocytes, which secrete adipokines that are known to influence different aspects of bone maintenance by regulating the differentiation or function of BMSCs, osteoblasts, or osteoclasts. Consistent with the idea that adipocyte-derived factors regulate osteoblast and osteoclast functions are the findings that bone mass is increased under conditions of generalized reduction in adipose tissue, as in the case of congenital lipodystrophy (Zou et al., 2019). However, the local secretion of adiponectin, an adipokine, in MAT appears to provide a stronger influence in this model (Zhong et al., 2020). Consistently, we did detect a decrease in adiponectin expression in the femurs of Ksr2 KO mice (data not shown). Nevertheless, this indicates that adipocytes can influence bone homeostasis by both systemic and local signals.

Leptin is another well-known adipokine secreted by adipocytes that is increased in obese animals and is known to regulate bone formation. However, a significant role for adipocyte-derived leptin in mediating the gains in trabecular bone mass in Ksr2 KO mice does not seem likely. We previously found that leptin is increased in serum of Ksr2 KO mice, but leptin resistance was not causative of weight gains in these mice (Costanzo-Garvey et al., 2009; Revelli et al., 2011). Here we show that leptin mRNA is increased in body fat depots but believe this is also not responsible for increased bone mass. Our data shows that pair-fed Ksr2 KO mice and osteoblast-specific conditional Ksr2 KO mice do not gain excess adipocytes, yet still resulted in gains in trabecular bone. Since leptin is produced by fat, which did not change in either of these conditions, these results suggest that gains in systemic leptin produced by excess fat may not be a causative factor in bone mass accretion when Ksr2 is deleted. Moreover, while we did see a reduction in leptin mRNA expression in femurs, in isolation this might be expected to reduce bone mass, given that in vitro and in vivo reports indicate that leptin is anabolic to limb bones (Astudillo et al., 2008; Gordeladze et al., 2002; Steppan et al., 2000; Wang et al., 2007a). While it has been reported that leptin mRNA is higher in visceral adipose tissue than BMAT (Liu et al., 2011), in the absence of KSR2, it is reduced even further, yet this does not result in bone loss.

Interestingly, MAT is significantly reduced in the long bones of Ksr2 KO mice compared to WT mice as revealed by osmium tetroxide microCT evaluation, as well as histological analyses of adipocyte numbers. By contrast, MAT has been shown to be increased in mice with disruption of leptin, leptin receptor, as well as mice fed with high-fat diets, all three models that show reduced femoral trabecular bone mass (Hamrick et al., 2004; Tencerova et al., 2018; Yue et al., 2016). These findings, together with the known fact that mesenchymal stem cells represent common precursors of both osteoblasts and adipocytes, raise the possibility that KSR2 might modulate the switch between osteoblast and adipocyte differentiation produced by mesenchymal stem cells, and, thereby, bone formation and MAT. Further studies are required to determine the cause-and-effect relationship between changes in Ksr2 expression and regulation of mesenchymal stem cell differentiation. In this regard, a recent study demonstrated that complement factor D/adipsin from bone marrow adipocytes regulates bone marrow stromal cell fate determination through activation of the complement system (Aaron et al., 2021). We, therefore, examined whether the expression of adipsin was altered in the bones of Ksr2 KO mice and found reduced expression of adipsin in both body fat and femoral adipocytes. The issue of whether KSR2 regulates adipsin expression directly or indirectly via other factors remains to be established. While Aaron et al. demonstrated that adipsin is a downstream target of PPARG, Pparg transcription was only mildly reduced in Ksr2 KO bones, thus raising the possibility that KSR2 might regulate adipsin expression independently of PPARG. BMSC fate decision is regulated by multiple factors, including many known, and potentially unknown, growth factors and hormones (Chen et al., 2016). Interestingly, non-endocrinological neural regulation mechanisms also contribute to MAT formation (Zhang et al., 2021). Also, factors secreted by osteoblasts such as osteopontin have been shown to locally regulate bone MAT (Chen et al., 2014a). Therefore, KSR2 might modulate BMSC fate by regulation of adipsin expression, as well as the response to signaling by other factors, which await further investigation.

Other factors that might affect bone physiology in obese and T2D conditions are inflammatory cytokines. While adipocytes are known to contribute to increased levels of pro-inflammatory cytokines such as TNF, Il6, Il17, and Tnfsf11/RANKL (Benova and Tencerova, 2020; Kawai et al., 2021) during certain pathological states that can promote increased osteoclastogenesis and resorptive activity, we did not see changes in bone resorption in Ksr2 KO mice. However, increased levels of these inflammatory cytokines could be responsible for the altered fracture healing in Ksr2 KO mice. Diet-induced obesity models have reported reduced callus bone volume and increased marrow adiposity, possibly due to a faster rate of callus resorption (Brown et al., 2014), producing bones with microstructural deficits in collagen matrix and increased advanced glycation end products (Khajuria et al., 2020). Although some studies find smaller callus in obesity/T2D fracture callus (Brown et al., 2014), others have also observed increased callus size in the fracture callus of DIO-obesity/T2D model fractures, with increased hypertrophic chondrocytes, and delayed fracture healing, similar to the results reported here (Marin et al., 2021). It is possible that fractures using an intramedullary pin are not as stabilized in the Ksr2 KO mice as that of WTs because of increased body weight, thus leading to a larger less dense callus, a phenomenon frequently seen in non-stabilized human fractures. Further time-course studies are needed to determine the cause for the delayed remodeling of fracture callus in the Ksr2 KO mice, and whether the healed bones in Ksr2 KO mice are mechanically weaker than the healed bones of control mice. Regardless, the diabetic state results in a deranged inflammatory condition that is believed to affect the vascular system by the production of advanced glycation end products and multiple factors that may delay fracture healing (Marin et al., 2018), and we show here that loss of Ksr2 may not be sufficient to impart improved fracture healing for diabetics. In the future, we will determine whether increased general adiposity is the cause of delayed fracture healing in global Ksr2 KO mice by evaluating whether fracture healing is affected in mice with conditional disruption of Ksr2 in osteoblasts. Nevertheless, bones of Ksr2 KO mice were less resistant to fracture, in agreement with the observation in obese/T2D humans that present with increased bone mass and fracture susceptibility (Greco et al., 2015; Ma et al., 2018; Moseley, 2012; Oei et al., 2013).

mTOR regulation of osteoblast formation remains controversial as both positive and negative associations have been reported (Chen et al., 2014b; Martin et al., 2010; Martin et al., 2015; Xian et al., 2012; Yeo et al., 2021). Our in vitro results show that forced expression of KSR2 reduces mTOR signaling, while knockdown of Ksr2 promotes induction of osteogenic factors, but not when mTOR signaling is inhibited by rapamycin. Moreover, both in vitro and in vivo results suggest that KSR2 and mTOR affect hypoxia but not Notch signaling genes. The anabolic effects of hypoxia signaling on bone mass and vasculature are well established (Mohan and Kesavan, 2022; Shen et al., 2009; Wan et al., 2010; Wang et al., 2007b; Wolf et al., 2022). Thus, whether the increased hypoxia signaling pathway observed in bones of Ksr2 KO mice contributes to the increased trabecular bone mass remains to be established. Thus, this work implicates mTOR as a positive effector of osteoblast differentiation that can be regulated by KSR2 (Figure 8I). Future studies are needed to determine how KSR2 regulates mTOR signaling biochemically, whether KSR2 regulates BMSC fate decision via mTOR in either the mTORC1 or mTORC2 complex, which is reportedly one means of affecting BMSC fate regulation (Martin et al., 2015; Sen et al., 2014), and whether osteoblast-specific deletion of mTOR in Ksr2 KO mice will reverse the bone gains in Ksr2 KO mice. Studies have shown that KSR2 is a scaffold protein that interacts with RAF and MEK to facilitate activation of ERK/MAPK module (Roy et al., 2002). In addition, a recent study demonstrated that KSR1 and KSR2 when expressed at high levels can activate the MAPK pathway-independent of RAS (Paniagua et al., 2022). Based on the published data that ERK effects on osteoblasts are mediated via mTOR signaling (Kim et al., 2022), it is possible that KSR2 effects on bone are via MAPK-mediated regulation of mTOR signaling. Our future studies will investigate this possibility.

In summary, our investigation of bones in Ksr2 knockout genetic mouse models resulted in the identification of a novel animal model in which the obesity/T2D condition coincides with increased appendicular bone mass. Since KSR2 genetic polymorphisms are linked to obesity/T2D in humans, our full understanding of how KSR2 differentially regulates general tissue adiposity versus bone marrow adiposity could lead to the identification of novel therapeutic strategies to promote bone health in humans with obesity/T2D.

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for all figures.

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Author details

1. Gustavo A Gomez

   VA Loma Linda Healthcare System, Loma Linda, United States

   Contribution

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

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9294-4276

2. Charles H Rundle

   1. VA Loma Linda Healthcare System, Loma Linda, United States
   2. Loma Linda University Medical Center, Loma Linda, United States

   Contribution

   Data curation, Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

3. Weirong Xing

   1. VA Loma Linda Healthcare System, Loma Linda, United States
   2. Loma Linda University Medical Center, Loma Linda, United States

   Contribution

   Formal analysis, Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

4. Chandrasekhar Kesavan

   1. VA Loma Linda Healthcare System, Loma Linda, United States
   2. Loma Linda University Medical Center, Loma Linda, United States

   Contribution

   Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

5. Sheila Pourteymoor

   VA Loma Linda Healthcare System, Loma Linda, United States

   Contribution

   Data curation, Formal analysis, Methodology

   Competing interests

   No competing interests declared

6. Robert E Lewis

   University of Nebraska Medical Center, Omaha, United States

   Contribution

   Resources, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3616-2971

7. David R Powell

   Lexicon Pharmaceuticals, The Woodlands, United States

   Contribution

   Resources, Investigation, Writing – review and editing

   Competing interests

   was employed by Lexicon Pharmaceuticals, Inc, at the time some of these studies were performed and may own common stock or have been granted stock options

   "This ORCID iD identifies the author of this article:" 0000-0003-0656-0124

8. Subburaman Mohan

   1. VA Loma Linda Healthcare System, Loma Linda, United States
   2. Loma Linda University Medical Center, Loma Linda, United States

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing - original draft, Project administration, Writing – review and editing

   For correspondence

   Subburaman.Mohan@va.gov

   Competing interests

   Reviewing editor, eLife

   "This ORCID iD identifies the author of this article:" 0000-0003-0063-986X

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