The mutual dependence between bone and gonads

in Journal of Endocrinology

It has long been known that sex steroid hormones regulate bone mass accrual. This observation raises the testable hypothesis that bone may in turn regulate the synthesis and secretion of sex steroid hormones in one or both genders. This hypothesis is comprised within a more general hypothesis that bone mass, energy metabolism, and reproduction are regulated coordinately. The identification of osteocalcin as an osteoblast-specific secreted molecule allows us to address this question in molecular terms. This review details how the regulation of male fertility by osteocalcin was unraveled, and how osteocalcin signaling in Leydig cells of the testis occurs. It also discusses the implication of this novel mode of regulation of testosterone synthesis observed in males but not in females.

Abstract

It has long been known that sex steroid hormones regulate bone mass accrual. This observation raises the testable hypothesis that bone may in turn regulate the synthesis and secretion of sex steroid hormones in one or both genders. This hypothesis is comprised within a more general hypothesis that bone mass, energy metabolism, and reproduction are regulated coordinately. The identification of osteocalcin as an osteoblast-specific secreted molecule allows us to address this question in molecular terms. This review details how the regulation of male fertility by osteocalcin was unraveled, and how osteocalcin signaling in Leydig cells of the testis occurs. It also discusses the implication of this novel mode of regulation of testosterone synthesis observed in males but not in females.

Introduction

The principle of mutual dependence between organs as an underlying notion of vertebrate physiology has been verified over and over through mouse genetics. It is clear nowadays that there are interconnections between the different organs in regulation of whole organism physiology. The organs need to communicate with each other to keep our body functional. Based on this view of physiology, it was recently demonstrated that bone is not only a recipient of hormonal inputs but also an endocrine organ of major importance. Multiple studies have shown that bone, via an osteoblast-secreted hormone called osteocalcin, promotes β-cell proliferation, insulin secretion, and insulin sensitivity in muscle, liver, and white adipose tissue (Lee et al. 2007, Im et al. 2008, Aonuma et al. 2009, Fernandez-Real et al. 2009, Hwang et al. 2009, Kanazawa et al. 2009, Kindblom et al. 2009, Pittas et al. 2009, Ferron et al. 2010, Rached et al. 2010, Winhofer et al. 2010, Yeap et al. 2010, Levinger et al. 2011).

It has long been recognized that bone mass accrual is profoundly regulated by sex steroid hormones, which are necessary for the bone growth and for the maintenance of skeletal integrity (Khosla et al. 2001, Riggs et al. 2002, Nakamura et al. 2007). The biological importance of this regulation is best exemplified by the fact that gonadal failure triggers bone loss in both genders. Estrogen deficiencies at menopause in women and androgen decrease in elderly men are the major pathogenic factors in the development of osteoporosis (Riggs et al. 1998, 2002, Khosla et al. 2001, Vanderschueren et al. 2004, Khosla & Riggs 2005, Nakamura et al. 2007, Khosla 2010a,b). Considering that endocrine regulation is often subjected to feedback loop mechanisms, the regulation of bone mass accrual by gonads suggests that bone, in its endocrine capacity, may affect the reproductive functions in one or both genders.

This review is a presentation of the unexpected influence the skeletal system exerts on male reproduction.

Sex steroid hormones regulate bone mass accrual

The sex steroid hormones estrogen and androgen have central roles in the control of sexual maturity and reproduction (Pincus 1962). In addition to their reproductive functions, sex steroid hormones are essential for skeletal development and the maintenance of bone health throughout adult life (Riggs et al. 2002, Vanderschueren et al. 2004, Vandenput & Ohlsson 2009). Testosterone and estrogen positively influence growth, maturation, and maintenance of the female and male skeleton (Riggs et al. 2002, Vanderschueren et al. 2004, Callewaert et al. 2010a). Their effects are mediated mainly by slow genomic mechanisms through nuclear hormonal receptors, and possibly through fast nongenomic mechanisms by membrane-associated receptors and signaling cascades (Riggs et al. 2002, Vanderschueren et al. 2004, Venken et al. 2008).

Sex steroid hormones regulate bone growth

Sex steroids play an important role in bone growth and the attainment of peak bone mass. They are, at least in part, responsible for the gender differences in bone growth, which emerges during adolescence (Riggs et al. 2002, Vanderschueren et al. 2004, Clarke & Khosla 2010). Although skeletal size and volume are similar in prepubertal girls and boys (Kelly et al. 1990, Seeman 2001, Vanderschueren et al. 2004, Kirmani et al. 2009, Callewaert et al. 2010a), the sexual dimorphism in bone growth becomes apparent during puberty, at which time men reach higher peak bone mass (Clarke & Khosla 2010). This skeletal sexual dimorphism is mainly due to a stimulatory androgen action on periosteal bone formation in men, whereas an inhibitory estrogen-related action occurs in women (Bertelloni et al. 1995, Finkelstein et al. 1996, Katznelson et al. 1996, Seeman 2001, Venken et al. 2006, Kirmani et al. 2009). Since an excess of androgen in women is associated with higher bone mineral density, there is evidence that androgens also affect peak bone mass in women (Buchanan et al. 1988, Zborowski et al. 2000, Wei et al. 2010).

In addition to the sex steroid hormones, several studies have shown that other hormones negatively regulated by estrogen, such as growth hormone (GH) and insulin-like growth factor 1 (IGF1), may further contribute to the development of the skeletal sexual dimorphism (Lupu et al. 2001, Venken et al. 2005, Callewaert et al. 2010a,b). IGF1 levels are higher in males vs females during early puberty (Callewaert et al. 2010b,c), and mice lacking GH receptor (GHR), IGF1, or both show a severe bone growth retardation (Lupu et al. 2001). These evidence strongly suggest that skeletal dimorphism in bone growth can not only be attributed to the differences in sex steroid hormone secretion and action in males and females, but also depends on complex gender- and time-specific interactions between several factors (Callewaert et al. 2010a).

Sex steroid hormones maintain skeletal integrity

Testosterone and estrogens are also crucial for maintaining bone mass accrual during adulthood in the female and male skeleton. The loss of ovarian function underlies the development of osteoporosis (Riggs et al. 2002, Vanderschueren et al. 2004). As a matter of fact, estrogen deficiency is a major pathogenic factor in the bone loss associated with menopause and the development of osteoporosis in postmenopausal women (Riggs et al. 1998, 2002, Khosla et al. 2001, Khosla & Riggs 2005, Nakamura et al. 2007). After menopause, an imbalance between rates of bone formation and bone resorption, favoring the latter, leads to an accelerated bone loss during the first years after menopause (Garnero et al. 1996, Clarke & Khosla 2010). This rapid bone loss can be prevented by estrogen administration, and characteristically results in an increase in bone mineral density during the first months of treatment (Lindsay et al. 1976, 1980, Stevenson et al. 1990). Additionally, the loss of testicular function also underlies bone loss in men. Although osteoporosis more commonly affects women, the loss of androgens in males following castration or a decrease in androgen levels related to aging has the same dramatic effect on the skeleton (Stepan et al. 1989, Riggs et al. 2002, Vanderschueren et al. 2004, Kaufman & Vermeulen 2005).

The traditional view of the sex steroid hormones presenting androgens and estrogens as a male and female hormones respectively has been reconsidered recently (Callewaert et al. 2010a). A series of evidence shows that estrogens may have a crucial role in the maintenance of bone mass accrual and skeletal homeostasis in elderly men (van den Beld et al. 2000, Bouillon et al. 2004, Mellstrom et al. 2006, Rochira et al. 2007, Araujo et al. 2008). These data suggest that the role of sex steroid hormones in age-related bone loss in women and men is the result of disturbances affecting a complex network regulating bone mass that remains to be further investigated.

Estrogen and androgen mode of action in skeleton

The sex steroid hormones may influence skeletal physiology, at least in part, by acting directly on bone cells via their classical receptors for estrogens or androgens (Noble et al. 1999, Vidal et al. 1999, Bord et al. 2001). However, mice deficient for ERα (αERKO), ERβ (βERKO), double ER (DERKO), and AR (ARKO) did not produce phenotypes similar to those observed in the absence of estrogen or androgen (Couse & Korach 1999, Couse et al. 1999, Oz et al. 2000, Vidal et al. 2000, Lindberg et al. 2001, Riggs et al. 2002, Vanderschueren et al. 2004, Callewaert et al. 2009). This may be explained by the fact that in these models the levels of sex steroid hormones are abnormally high, and/or that these hormones may also have nongenomic modes of action. Androgen and estrogen can transmit antiapoptotic effects on osteoblasts in vitro with a similar efficiency via either AR or ERs, irrespective of whether the ligand is an androgen or an estrogen (Kousteni et al. 2001, 2002, Manolagas et al. 2002). Hence, at the present time the mechanisms mediating estrogen and androgen function in the bone, via ERs and AR, are not fully elucidated.

Estrogens, mainly 17β-estradiol, are essential for the maintenance of the balance between bone formation and bone resorption (Riggs et al. 2002, Vanderschueren et al. 2004). At the cellular level, Estrogens affect the generation, lifespan, and functional activity of osteoclasts (Fig. 1). They decrease osteoclast formation and activity, while increasing osteoclast apoptosis (Fig. 1; Hughes et al. 1996, Imai et al. 2009). The role of estrogen regulation of osteoblasts is less clear, and investigations have produced conflicting results and thus will not be presented here. At the molecular level, Estrogens favor osteoclast apoptosis by decreasing the production of cytokines, such as interleukin 1 (IL1), IL6, tumor necrosis factor a (TNFα), and macrophage colony-stimulating factor (Hughes et al. 1996, Jimi et al. 1996, Pacifici 1996, Manolagas et al. 2002, Riggs et al. 2002, Xing & Boyce 2005). In addition, Estrogens suppress bone resorption by inhibiting the osteoclast activity (Fig. 1). Estrogens enhance the expression of transforming growth factor (TGF)-β and OPG, inhibitors of osteoclast activity, while decreasing the expression of RANKL, an activator of osteoclast activity (Bodine et al. 1995, Gill et al. 1998, Tau et al. 1998, Michael et al. 2005). Lastly, Estrogens suppress osteoclast formation by upregulating expression of Fas ligand (Fasl), a gene that belongs to the TNF family (Nakamura et al. 2007, Krum et al. 2008). Therefore, estrogens actions are important physiological regulators of bone remodeling during adulthood.

Figure 1

Download Figure

Figure 1

Gonads regulate bone physiology via the sex steroid hormones they produce. Testosterone and estrogen secreted by gonads are essential for the skeletal growth, maturation, and maintenance in both men and women. The sex steroid hormones regulate the apoptosis and/or proliferation of osteoblasts and/or osteoclasts.

Citation: Journal of Endocrinology 213, 2; 10.1530/JOE-11-0452

Androgens favor periostal bone formation in men, and maintain trabecular bone mass and integrity (Fig. 1). At the cellular level, testosterone increases the lifespan of osteoblasts (Fig. 1) by inhibiting IL6 production (Jilka et al. 1992, Manolagas et al. 2002). Furthermore, androgens stimulate the proliferation of osteoblast progenitors and the differentiation of mature osteoblasts (Fig. 1; Kasperk et al. 1989, Kousteni et al. 2001, 2002, Manolagas et al. 2002). At the molecular level, some evidence indicates that androgens favor osteoblast proliferation and differentiation (Fig. 1) by increasing TGF-β mRNA, as well as promoting responsiveness to fibroblast growth factor and IGF2 (Bodine et al. 1995, Gill et al. 1998, Riggs et al. 2002). Androgens may also decrease osteoclast formation and bone resorption (Fig. 1) by increasing the production of OPG by osteoblasts (Michael et al. 2005). The net result of these testosterone functions leads to an accrual in bone formation (Fig. 1; Seeman 2001).

The skeleton regulates gonadal functions in males

The view of bone merely as an assembly of inert calcified tubes characterized only by its scaffolding properties has proven to be wrong. As a matter of fact, the skeleton has emerged in recent years as an endocrine organ of major importance. Multiple studies have shown that osteocalcin, an osteoblast-specific secreted hormone, promotes β-cell proliferation, insulin secretion, and insulin sensitivity in muscle, liver, and white adipose tissue (Lee et al. 2007, Ferron et al. 2010, Fulzele et al. 2010). Remarkably, it has also been shown that another gene expressed in osteoblasts, Esp (Ptprv), encoding a tyrosine phosphatase called OST-PTP (osteotesticular protein tyrosine phosphatase) exerts metabolic functions opposite to those of osteocalcin (Lee et al. 2007). Genetic and biochemical evidence put OST-PTP as an upstream negative regulator of osteocalcin bioactivity in osteoblasts (Lee et al. 2007, Ferron et al. 2008, 2010, Hinoi et al. 2008, Fulzele et al. 2010). Indeed, Esp−/− mice had a metabolic phenotype that is the mirror image of that of Osteocalcin−/− mice (Lee et al. 2007, Ferron et al. 2008).

The hormonal functions of osteocalcin as a bone-derived molecule have raised a number of questions of biological and clinical relevance. The most pressing one was to determine if the skeleton has physiological functions in addition to those exerted on energy metabolism and glucose homeostasis. As mentioned above, that menopause favors bone loss is well established (Riggs et al. 1998, 2002, Khosla et al. 2001, Vanderschueren et al. 2004, Khosla & Riggs 2005, Nakamura et al. 2007, Khosla 2010a,b). What this medical observation means biologically, as discussed previously, is that gonads regulate bone physiology through the secretion of sex steroid hormones. According to the general principle of feedback control, the regulation of bone mass accrual by gonads implies that bone may affect the reproductive functions in one or both genders. Verifying this hypothesis was of great conceptual importance as it would further enhance the emerging importance of bone as an endocrine organ.

The first evidence supporting this hypothesis came from ex vivo cell assays. Indeed, these studies demonstrated that a factor secreted by osteoblats, but not by other cells of mesodermal origin, could markedly increase testosterone production in testis explants and primary Leydig cells (Oury et al. 2011). The effect of osteoblast supernatants was limited to males; osteoblasts did not stimulate testosterone or estrogens secretion in females. Recently, this novel and important role of osteoblasts has been verified in vivo. Using DTAosb mice, an osteoblast-less mouse model, ablation of osteoblasts in adult mice profoundly affects circulating testosterone levels (Yoshikawa et al. 2011).

Osteocalcin regulates testosterone biosynthesis

Since osteocalcin has an important role in the regulation of energy metabolism and glucose homeostasis, it was hypothesized that it may also affect testosterone production. Several experiments have confirmed this hypothesis in vitro and ex vivo. First, using the same co-culture assays described above, the supernatants of wild-type (WT) but not those of Osteocalcin−/− osteoblasts increased testosterone production in testis explants and primary Leydig cells cultures (Oury et al. 2011). Secondly, treating primary Leydig cells with an increasing amount of undercarboxylated osteocalcin, the active form of the hormone, resulted in a dose-dependent increase in testosterone secretion (Oury et al. 2011). Thirdly, injection of osteocalcin in WT mice significantly increased circulating levels of testosterone (Oury et al. 2011). Lastly, administration of osteocalcin in mice lacking osteoblasts fully restored testosterone to normal serum levels (Yoshikawa et al. 2011).

A role for osteocalcin in the regulation of testosterone biosynthesis was also demonstrated in vivo (Lee et al. 2007). Osteocalcin−/− mice showed a severe decrease in testis and epidymidal weights, as well as sperm count. These features are associated with the low circulating testosterone levels observed in Osteocalcin−/ mice (Oury et al. 2011). Perhaps and more surprisingly, serum luteinizing hormone (LH) levels (the major regulator of testosterone production) were higher in Osteocalcin−/− compared to WT male mice. These data suggest a compensatory mechanism is functioning that is insufficient to rescue testosterone production in Osteocalcin−/− mice (Oury et al. 2011). In contrast, analyses of Osteocalcin−/− female mice did not show any abnormalities in ovarian, cycling, or in circulating levels of the sex steroid hormones (Oury et al. 2011). These observations suggest that the role of osteocalcin on testosterone production is male specific, and that it acts through a receptor expressed in testis but not in ovaries.

Regulation of sex steroid secretion is subject to feedback inhibition. Indeed, the aromatization of testosterone to estradiol is a large contributing factor to feedback inhibition of testosterone secretion (Schnorr et al. 2001). Accordingly, aromatase inhibition in males results in rather large increases in LH and follicle-stimulating hormone, causing subsequent elevations in testosterone (Leder et al. 2004, T'Sjoen et al. 2005). Interestingly, Osteocalcin-deficient male mice also have significantly increased levels of circulating estradiol leading to a disturbance in testosterone/estradiol ratio (Oury et al. 2011). This observation suggests that osteocalcin may be involved in one of the major mechanisms of feedback inhibition of testosterone secretion. This hypothesis needs to be further investigated.

In summary, these experiments established that osteocalcin is a bone-derived hormone favoring fertility in male mice by promoting testosterone production in Leydig cells (Fig. 2). In other words, it verified that, in at least one gender, there is an endocrine regulation of reproduction by the skeleton (Fig. 2). It also suggests that there may be differences between males and females in the regulation of this function.

Figure 2

Download Figure

Figure 2

Bone via osteocalcin, an osteoblast-derived hormone, regulates testosterone production in testis. Following its binding to a GPRC6A expressed on Leydig cells of the testes, osteocalcin promotes in a cAMP-response element binding protein (CREB)-dependent manner testosterone production by testis. CREB binds to the promoter regions and activates the expression of several genes encoding for the enzymes that are necessary for testosterone biosynthesis, such as STAR, CYP11A, 3β-HSD, and CYP17. Steroidogenic acute regulatory protein (StAR) is crucial for transport of cholesterol to mitochondria where biosynthesis of steroids is initiated. CYP11A encodes the cholesterol side-chain cleavage enzyme (P450scc) that catalyzes the first and rate-limiting step, which converts cholesterol to pregnenolone. 3β-HSD and CYP17 encode two enzymes required during the conversion of pregnenolone to testosterone. Testosterone is a sex steroid hormone required for many aspects of testicular functions, such as germ cell survival and spermatogenesis.

Citation: Journal of Endocrinology 213, 2; 10.1530/JOE-11-0452

Osteocalcin acts on Leydig cells through its receptor GPRC6A

Once the demonstration of the existence of an osteocalcin/testosterone axis was made in vivo, the most important question has been to know its mechanisms of action in testis. In a first attempt to address this question, it was shown that osteocalcin enhances the production cAMP in the β-cell of the pancreas and in the Leydig cell of the testis. This observation suggested that the, or at least an, osteocalcin receptor would be a G protein-coupled receptor (GPCR) linked to adenylate cyclase. One GPCR, GPRC6A, was a particularly good candidate to be an osteocalcin receptor since Dr Quarles's group has shown that its inactivation in mice results in metabolic and reproduction phenotypes similar to those seen in Osteocalcin−/− mice (Pi et al. 2008). The inactivation of Gprc6a in mice leads to an increase in adiposity, decrease in muscle mass, and low circulating testosterone levels associated with elevated estradiol serum levels in male mice (Pi et al. 2008, Oury et al. 2011). Furthermore, it was proposed that GPRC6A was a calcium-sensing receptor that functioned better in the presence of osteocalcin (Pi et al. 2008). In testing this hypothesis in mice, it was first shown that osteocalcin binds to WT but not to Gprc6a-deficient Leydig cells. Secondly, osteocalcin did not stimulate cAMP production in Gprc6a-deficient Leydig cells (Oury et al. 2011). Thirdly, compound heterozygous mice lacking one copy of osteocalcin and one copy of Gprc6a (Osteocalcin+/−; Gprc6a+/−) showed a reproduction phenotype similar, if not identical, in all aspects that observed in osteocalcin−/− or Gprc6a−/− mice (Pi et al. 2008, Oury et al. 2011). Lastly, analyzing the role of osteocalcin in regulation of energy metabolism demonstrated that GPRC6A mediates responses to osteocalcin in β-cells in vitro, and pancreas in vivo (Pi et al. 2011).

According to the studies of three different groups, Gprc6a is expressed in brain, skeletal muscle, heart, lung, spleen, kidney, liver, fat, and pancreatic β-cells (Wellendorph & Brauner-Osborne 2004, Kuang et al. 2005, Pi et al. 2005, 2008). It is known that osteocalcin can stimulate insulin secretion in β-cells and promote insulin sensitivity in peripheral tissues including liver, fat, and muscle (Lee et al. 2007, Ferron et al. 2008). Whether osteocalcin acts on the other tissues expressing Gprc6a remains to be determined. Interestingly, GPRC6A is not expressed in ovaries (Oury et al. 2011). This restricted pattern of expression in gonads may explain why osteocalcin can increase testosterone production from testis, but not from ovaries. The investigation of the role of Gprc6a in regulation of bone mass accrual has generated contradicting findings (Pi et al. 2008, 2010, Wellendorph et al. 2009), and thus this aspect of Gprc6a function will not be developed further in this review.

Investigating the downstream cascade mediated by GPRC6A as an osteocalcin receptor led to the identification of cAMP response element binding protein (CREB) as a transcriptional effector of osteocalcin regulation of testosterone biosynthesis (Fig. 2; Oury et al. 2011). The activation of CREB by osteocalcin signaling favors the expression of key enzymes of testosterone biosynthetic pathway in Leydig cells, such as STAR, CYP11A (CYP11A1), CYP17 (CYP17A1), and 3β-HSD (Fig. 2; Oury et al. 2011). Interestingly, the inactivation of osteocalcin in mice does not affect the expression of the aromatase gene, Cyp19a, responsible for estrogen synthesis (Oury et al. 2011).

Conclusion

The unraveling of this novel endocrine role of the skeleton indicates that no organ is left out of the integrating processes required to allow vertebrates to fulfil their physiological functions. This is consistent with the idea that organisms are integrated entities fulfilling their specific functions, and not as isolated group of distinct cell types. When this concept was applied to the skeleton it has yielded surprising results. But, are these findings really surprising? As a matter of fact, if one considers the unique features of bone and the energetic cost that the perpetual cycle of destruction/formation that characterizing bone modeling and remodeling entails, one might find them not so surprising. Rather it serves as a reminder that physiology has to be studied in the context of evolution, the original purpose of physiological functions being to allow survival, in that case bone growth and ambulation, in difficult conditions and not under the light of degenerative diseases that did not exist when these functions emerged.

This foray in bone physiology is evidence that asking why a given physiological function was created may lead to further discovery of interorgan connections. This in turn may allow a better understanding of the pathogenesis of degenerative diseases, and possibly the design of adapted therapies for these diseases. This is the ultimate purpose of an integrated approach physiology illustrated in this review.

Declaration of interest

The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.

Funding

This work was supported by the NIH Grant (grant number: 5 R01 DK058883).

References

  • AonumaHMiyakoshiNHongoMKasukawaYShimadaY2009Low serum levels of undercarboxylated osteocalcin in postmenopausal osteoporotic women receiving an inhibitor of bone resorption. Tohoku Journal of Experimental Medicine218201205. doi:10.1620/tjem.218.201.

  • AraujoABTravisonTGLederBZMcKinlayJB2008Correlations between serum testosterone, estradiol, and sex hormone-binding globulin and bone mineral density in a diverse sample of men. Journal of Clinical Endocrinology and Metabolism9321352141. doi:10.1210/jc.2007-1469.

  • van den BeldAWde JongFHGrobbeeDEPolsHALambertsSW2000Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men. Journal of Clinical Endocrinology and Metabolism8532763282. doi:10.1210/jc.85.9.3276.

  • BertelloniSBaroncelliGIBattiniRPerriGSaggeseG1995Short-term effect of testosterone treatment on reduced bone density in boys with constitutional delay of puberty. Journal of Bone and Mineral Research1014881495. doi:10.1002/jbmr.5650101009.

  • BodinePVRiggsBLSpelsbergTC1995Regulation of c-fos expression and TGF-β production by gonadal and adrenal androgens in normal human osteoblastic cells. Journal of Steroid Biochemistry and Molecular Biology52149158. doi:10.1016/0960-0760(94)00165-I.

  • BordSHornerABeavanSCompstonJ2001Estrogen receptors α and β are differentially expressed in developing human bone. Journal of Clinical Endocrinology and Metabolism8623092314. doi:10.1210/jc.86.5.2309.

  • BouillonRBexMVanderschuerenDBoonenS2004Estrogens are essential for male pubertal periosteal bone expansion. Journal of Clinical Endocrinology and Metabolism8960256029. doi:10.1210/jc.2004-0602.

  • BuchananJRMyersCLloydTLeuenbergerPDemersLM1988Determinants of peak trabecular bone density in women: the role of androgens, estrogen, and exercise. Journal of Bone and Mineral Research3673680. doi:10.1002/jbmr.5650030613.

  • CallewaertFVenkenKOphoffJDe GendtKTorcasioAvan LentheGHVan OosterwyckHBoonenSBouillonRVerhoevenG2009Differential regulation of bone and body composition in male mice with combined inactivation of androgen and estrogen receptor-α. FASEB Journal23232240. doi:10.1096/fj.08-113456.

  • CallewaertFBoonenSVanderschuerenD2010aSex steroids and the male skeleton: a tale of two hormones. Trends in Endocrinology and Metabolism218995. doi:10.1016/j.tem.2009.09.002.

  • CallewaertFSinnesaelMGielenEBoonenSVanderschuerenD2010bSkeletal sexual dimorphism: relative contribution of sex steroids, GH–IGF1, and mechanical loading. Journal of Endocrinology207127134. doi:10.1677/JOE-10-0209.

  • CallewaertFVenkenKKopchickJJTorcasioAvan LentheGHBoonenSVanderschuerenD2010cSexual dimorphism in cortical bone size and strength but not density is determined by independent and time-specific actions of sex steroids and IGF-1: evidence from pubertal mouse models. Journal of Bone and Mineral Research25617626. doi:10.1359/jbmr.090828.

  • ClarkeBLKhoslaS2010Physiology of bone loss. Radiologic Clinics of North America48483495. doi:10.1016/j.rcl.2010.02.014.

  • CouseJFKorachKS1999Estrogen receptor null mice: what have we learned and where will they lead us?Endocrine Reviews20358417. doi:10.1210/er.20.3.358.

  • CouseJFHewittSCBunchDOSarMWalkerVRDavisBJKorachKS1999Postnatal sex reversal of the ovaries in mice lacking estrogen receptors α and β. Science28623282331. doi:10.1126/science.286.5448.2328.

  • Fernandez-RealJMIzquierdoMOrtegaFGorostiagaEGomez-AmbrosiJMoreno-NavarreteJMFruhbeckGMartinezCIdoateFSalvadorJ2009The relationship of serum osteocalcin concentration to insulin secretion, sensitivity, and disposal with hypocaloric diet and resistance training. Journal of Clinical Endocrinology and Metabolism94237245. doi:10.1210/jc.2008-0270.

  • FerronMHinoiEKarsentyGDucyP2008Osteocalcin differentially regulates β cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. PNAS10552665270. doi:10.1073/pnas.0711119105.

  • FerronMWeiJYoshizawaTDel FattoreADePinhoRATetiADucyPKarsentyG2010Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell142296308. doi:10.1016/j.cell.2010.06.003.

  • FinkelsteinJSKlibanskiANeerRM1996A longitudinal evaluation of bone mineral density in adult men with histories of delayed puberty. Journal of Clinical Endocrinology and Metabolism8111521155. doi:10.1210/jc.81.3.1152.

  • FulzeleKRiddleRCDiGirolamoDJCaoXWanCChenDFaugereMCAjaSHussainMABruningJC2010Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell142309319. doi:10.1016/j.cell.2010.06.002.

  • GarneroPSornay-RenduEChapuyMCDelmasPD1996Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. Journal of Bone and Mineral Research11337349. doi:10.1002/jbmr.5650110307.

  • GillRKTurnerRTWronskiTJBellNH1998Orchiectomy markedly reduces the concentration of the three isoforms of transforming growth factor β in rat bone, and reduction is prevented by testosterone. Endocrinology139546550. doi:10.1210/en.139.2.546.

  • HinoiEGaoNJungDYYadavVYoshizawaTMyersMGJrChuaSCJrKimJKKaestnerKHKarsentyG2008The sympathetic tone mediates leptin's inhibition of insulin secretion by modulating osteocalcin bioactivity. Journal of Cell Biology18312351242. doi:10.1083/jcb.200809113.

  • HughesDEDaiATiffeeJCLiHHMundyGRBoyceBF1996Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-β. Nature Medicine211321136. doi:10.1038/nm1096-1132.

  • HwangYCJeongIKAhnKJChungHY2009The uncarboxylated form of osteocalcin is associated with improved glucose tolerance and enhanced β-cell function in middle-aged male subjects. Diabetes/Metabolism Research and Reviews25768772. doi:10.1002/dmrr.1045.

  • ImJAYuBPJeonJYKimSH2008Relationship between osteocalcin and glucose metabolism in postmenopausal women. Clinica Chimica Acta3966669. doi:10.1016/j.cca.2008.07.001.

  • ImaiYYounMYKondohSNakamuraTKouzmenkoAMatsumotoTTakadaITakaokaKKatoS2009Estrogens maintain bone mass by regulating expression of genes controlling function and life span in mature osteoclasts. Annals of the New York Academy of Sciences1173 (Suppl 1) E31E39. doi:10.1111/j.1749-6632.2009.04954.x.

  • JilkaRLHangocGGirasoleGPasseriGWilliamsDCAbramsJSBoyceBBroxmeyerHManolagasSC1992Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science2578891. doi:10.1126/science.1621100.

  • JimiEIkebeTTakahashiNHirataMSudaTKogaT1996Interleukin-1α activates an NF-kappaB-like factor in osteoclast-like cells. Journal of Biological Chemistry27146054608. doi:10.1074/jbc.271.9.4605.

  • KanazawaIYamaguchiTYamamotoMYamauchiMKuriokaSYanoSSugimotoT2009Serum osteocalcin level is associated with glucose metabolism and atherosclerosis parameters in type 2 diabetes mellitus. Journal of Clinical Endocrinology and Metabolism944549. doi:10.1210/jc.2008-1455.

  • KasperkCHWergedalJEFarleyJRLinkhartTATurnerRTBaylinkDJ1989Androgens directly stimulate proliferation of bone cells in vitro. Endocrinology12415761578. doi:10.1210/endo-124-3-1576.

  • KatznelsonLFinkelsteinJSSchoenfeldDARosenthalDIAndersonEJKlibanskiA1996Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. Journal of Clinical Endocrinology and Metabolism8143584365. doi:10.1210/jc.81.12.4358.

  • KaufmanJMVermeulenA2005The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocrine Reviews26833876. doi:10.1210/er.2004-0013.

  • KellyPJTwomeyLSambrookPNEismanJA1990Sex differences in peak adult bone mineral density. Journal of Bone and Mineral Research511691175. doi:10.1002/jbmr.5650051112.

  • KhoslaS2010aUpdate in male osteoporosis. Journal of Clinical Endocrinology and Metabolism95310. doi:10.1210/jc.2009-1740.

  • KhoslaS2010bUpdate on estrogens and the skeleton. Journal of Clinical Endocrinology and Metabolism9535693577. doi:10.1210/jc.2010-0856.

  • KhoslaSRiggsBL2005Pathophysiology of age-related bone loss and osteoporosis. Endocrinology and Metabolism Clinics of North America3410151030 xi. doi:10.1016/j.ecl.2005.07.009.

  • KhoslaSMeltonLJIIIAtkinsonEJO'FallonWM2001Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. Journal of Clinical Endocrinology and Metabolism8635553561. doi:10.1210/jc.86.8.3555.

  • KindblomJMOhlssonCLjunggrenOKarlssonMKTivestenASmithUMellstromD2009Plasma osteocalcin is inversely related to fat mass and plasma glucose in elderly Swedish men. Journal of Bone and Mineral Research24785791. doi:10.1359/jbmr.081234.

  • KirmaniSChristenDvan LentheGHFischerPRBouxseinMLMcCreadyLKMeltonLJIIIRiggsBLAminSMullerR2009Bone structure at the distal radius during adolescent growth. Journal of Bone and Mineral Research2410331042. doi:10.1359/jbmr.081255.

  • KousteniSBellidoTPlotkinLIO'BrienCABodennerDLHanLHanKDiGregorioGBKatzenellenbogenJAKatzenellenbogenBS2001Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell104719730.

  • KousteniSChenJRBellidoTHanLAliAAO'BrienCAPlotkinLFuQMancinoATWenY2002Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science298843846. doi:10.1126/science.1074935.

  • KrumSAMiranda-CarboniGAHauschkaPVCarrollJSLaneTFFreedmanLPBrownM2008Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival. EMBO Journal27535545. doi:10.1038/sj.emboj.7601984.

  • KuangDYaoYLamJTsushimaRGHampsonDR2005Cloning and characterization of a family C orphan G-protein coupled receptor. Journal of Neurochemistry93383391. doi:10.1111/j.1471-4159.2005.03025.x.

  • LederBZRohrerJLRubinSDGalloJLongcopeC2004Effects of aromatase inhibition in elderly men with low or borderline-low serum testosterone levels. Journal of Clinical Endocrinology and Metabolism8911741180. doi:10.1210/jc.2003-031467.

  • LeeNKSowaHHinoiEFerronMAhnJDConfavreuxCDacquinRMeePJMcKeeMDJungDY2007Endocrine regulation of energy metabolism by the skeleton. Cell130456469. doi:10.1016/j.cell.2007.05.047.

  • LevingerIZebazeRJerumsGHareDLSeligSSeemanE2011The effect of acute exercise on undercarboxylated osteocalcin in obese men. Osteoporosis International2216211626. doi:10.1007/s00198-010-1370-7.

  • LindbergMKAlataloSLHalleenJMMohanSGustafssonJAOhlssonC2001Estrogen receptor specificity in the regulation of the skeleton in female mice. Journal of Endocrinology171229236. doi:10.1677/joe.0.1710229.

  • LindsayRHartDMAitkenJMMacDonaldEBAndersonJBClarkeAC1976Long-term prevention of postmenopausal osteoporosis by oestrogen. Evidence for an increased bone mass after delayed onset of oestrogen treatment. Lancet110381041. doi:10.1016/S0140-6736(76)92217-0.

  • LindsayRHartDMForrestCBairdC1980Prevention of spinal osteoporosis in oophorectomised women. Lancet211511154. doi:10.1016/S0140-6736(80)92592-1.

  • LupuFTerwilligerJDLeeKSegreGVEfstratiadisA2001Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. Developmental Biology229141162. doi:10.1006/dbio.2000.9975.

  • ManolagasSCKousteniSJilkaRL2002Sex steroids and bone. Recent Progress in Hormone Research57385409. doi:10.1210/rp.57.1.385.

  • MellstromDJohnellOLjunggrenOErikssonALLorentzonMMallminHHolmbergARedlund-JohnellIOrwollEOhlssonC2006Free testosterone is an independent predictor of BMD and prevalent fractures in elderly men: MrOS Sweden. Journal of Bone and Mineral Research21529535. doi:10.1359/jbmr.060110.

  • MichaelHHarkonenPLVaananenHKHentunenTA2005Estrogen and testosterone use different cellular pathways to inhibit osteoclastogenesis and bone resorption. Journal of Bone and Mineral Research2022242232. doi:10.1359/JBMR.050803.

  • NakamuraTImaiYMatsumotoTSatoSTakeuchiKIgarashiKHaradaYAzumaYKrustAYamamotoY2007Estrogen prevents bone loss via estrogen receptor α and induction of Fas ligand in osteoclasts. Cell130811823. doi:10.1016/j.cell.2007.07.025.

  • NobleBRoutledgeJStevensHHughesIJacobsonW1999Androgen receptors in bone-forming tissue. Hormone Research513136. doi:10.1159/000023310.

  • OuryFSumaraGSumaraOFerronMChangHSmithCEHermoLSuarezSRothBLDucyP2011Endocrine regulation of male fertility by the skeleton. Cell144796809. doi:10.1016/j.cell.2011.02.004.

  • OzOKZerwekhJEFisherCGravesKNanuLMillsapsRSimpsonER2000Bone has a sexually dimorphic response to aromatase deficiency. Journal of Bone and Mineral Research15507514. doi:10.1359/jbmr.2000.15.3.507.

  • PacificiR1996Estrogen, cytokines, and pathogenesis of postmenopausal osteoporosis. Journal of Bone and Mineral Research1110431051. doi:10.1002/jbmr.5650110802.

  • PiMFaberPEkemaGJacksonPDTingAWangNFontilla-PooleMMaysRWBrundenKRHarringtonJJ2005Identification of a novel extracellular cation-sensing G-protein-coupled receptor. Journal of Biological Chemistry2804020140209.

  • PiMChenLHuangMZZhuWRinghoferBLuoJChristensonLLiBZhangJJacksonPD2008GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome. PLoS ONE3e3858doi:10.1371/journal.pone.0003858.

  • PiMZhangLLeiSFHuangMZZhuWZhangJShenHDengHWQuarlesLD2010Impaired osteoblast function in GPRC6A null mice. Journal of Bone and Mineral Research2510921102.

  • PiMWuYQuarlesLD2011GPRC6A mediates responses to osteocalcin in β-cells in vitro and pancreas in vivo. Journal of Bone and Mineral Research2616801683. doi:10.1002/jbmr.390.

  • PincusG1962Reproduction. Annual Review of Physiology245784. doi:10.1146/annurev.ph.24.030162.000421.

  • PittasAGHarrisSSEliadesMStarkPDawson-HughesB2009Association between serum osteocalcin and markers of metabolic phenotype. Journal of Clinical Endocrinology and Metabolism94827832. doi:10.1210/jc.2008-1422.

  • RachedMTKodeAXuLYoshikawaYPaikJHDepinhoRAKousteniS2010FoxO1 is a positive regulator of bone formation by favoring protein synthesis and resistance to oxidative stress in osteoblasts. Cell Metabolism11147160. doi:10.1016/j.cmet.2010.01.001.

  • RiggsBLO'FallonWMMuhsJO'ConnorMKKumarRMeltonLJIII1998Long-term effects of calcium supplementation on serum parathyroid hormone level, bone turnover, and bone loss in elderly women. Journal of Bone and Mineral Research13168174. doi:10.1359/jbmr.1998.13.2.168.

  • RiggsBLKhoslaSMeltonLJIII2002Sex steroids and the construction and conservation of the adult skeleton. Endocrine Reviews23279302. doi:10.1210/er.23.3.279.

  • RochiraVZirilliLMadeoBArandaCCaffagniGFabreBMontangeroVERoldanEJMaffeiLCaraniC2007Skeletal effects of long-term estrogen and testosterone replacement treatment in a man with congenital aromatase deficiency: evidences of a priming effect of estrogen for sex steroids action on bone. Bone4016621668. doi:10.1016/j.bone.2007.01.022.

  • SchnorrJABrayMJVeldhuisJD2001Aromatization mediates testosterone's short-term feedback restraint of 24-hour endogenously driven and acute exogenous gonadotropin-releasing hormone-stimulated luteinizing hormone and follicle-stimulating hormone secretion in young men. Journal of Clinical Endocrinology and Metabolism8626002606. doi:10.1210/jc.86.6.2600.

  • SeemanE2001Clinical review 137: sexual dimorphism in skeletal size, density, and strength. Journal of Clinical Endocrinology and Metabolism8645764584. doi:10.1210/jc.86.10.4576.

  • StepanJJLachmanMZverinaJPacovskyVBaylinkDJ1989Castrated men exhibit bone loss: effect of calcitonin treatment on biochemical indices of bone remodeling. Journal of Clinical Endocrinology and Metabolism69523527. doi:10.1210/jcem-69-3-523.

  • StevensonJCCustMPGangarKFHillardTCLeesBWhiteheadMI1990Effects of transdermal versus oral hormone replacement therapy on bone density in spine and proximal femur in postmenopausal women. Lancet336265269. doi:10.1016/0140-6736(90)91801-G.

  • TauKRHefferanTEWatersKMRobinsonJASubramaniamMRiggsBLSpelsbergTC1998Estrogen regulation of a transforming growth factor-β inducible early gene that inhibits deoxyribonucleic acid synthesis in human osteoblasts. Endocrinology13913461353. doi:10.1210/en.139.3.1346.

  • T'SjoenGGGiagulliVADelvaHCrabbePDe BacquerDKaufmanJM2005Comparative assessment in young and elderly men of the gonadotropin response to aromatase inhibition. Journal of Clinical Endocrinology and Metabolism9057175722. doi:10.1210/jc.2005-0982.

  • VandenputLOhlssonC2009Estrogens as regulators of bone health in men. Nature Reviews. Endocrinology5437443. doi:10.1038/nrendo.2009.112.

  • VanderschuerenDVandenputLBoonenSLindbergMKBouillonROhlssonC2004Androgens and bone. Endocrine Reviews25389425. doi:10.1210/er.2003-0003.

  • VenkenKSchuitFVan LommelLTsukamotoKKopchickJJCoschiganoKOhlssonCMoverareSBoonenSBouillonR2005Growth without growth hormone receptor: estradiol is a major growth hormone-independent regulator of hepatic IGF-I synthesis. Journal of Bone and Mineral Research2021382149. doi:10.1359/JBMR.050811.

  • VenkenKDe GendtKBoonenSOphoffJBouillonRSwinnenJVVerhoevenGVanderschuerenD2006Relative impact of androgen and estrogen receptor activation in the effects of androgens on trabecular and cortical bone in growing male mice: a study in the androgen receptor knockout mouse model. Journal of Bone and Mineral Research21576585. doi:10.1359/jbmr.060103.

  • VenkenKCallewaertFBoonenSVanderschuerenD2008Sex hormones, their receptors and bone health. Osteoporosis International1915171525. doi:10.1007/s00198-008-0609-z.

  • VidalOKindblomLGOhlssonC1999Expression and localization of estrogen receptor-β in murine and human bone. Journal of Bone and Mineral Research14923929. doi:10.1359/jbmr.1999.14.6.923.

  • VidalOLindbergMKHollbergKBaylinkDJAnderssonGLubahnDBMohanSGustafssonJAOhlssonC2000Estrogen receptor specificity in the regulation of skeletal growth and maturation in male mice. PNAS9754745479. doi:10.1073/pnas.97.10.5474.

  • WeiSJonesGThomsonROtahalPDwyerTVennA2010Menstrual irregularity and bone mass in premenopausal women: cross-sectional associations with testosterone and SHBG. BMC Musculoskeletal Disorders11288doi:10.1186/1471-2474-11-288.

  • WellendorphPBrauner-OsborneH2004Molecular cloning, expression, and sequence analysis of GPRC6A, a novel family C G-protein-coupled receptor. Gene3353746. doi:10.1016/j.gene.2004.03.003.

  • WellendorphPJohansenLDJensenAACasanovaEGassmannMDeprezPClement-LacroixPBettlerBBrauner-OsborneH2009No evidence for a bone phenotype in GPRC6A knockout mice under normal physiological conditions. Journal of Molecular Endocrinology42215223. doi:10.1677/JME-08-0149.

  • WinhoferYHandisuryaATuraABittighoferCKleinKSchneiderBBieglmayerCWagnerOFPaciniGLugerA2010Osteocalcin is related to enhanced insulin secretion in gestational diabetes mellitus. Diabetes Care33139143. doi:10.2337/dc09-1237.

  • XingLBoyceBF2005Regulation of apoptosis in osteoclasts and osteoblastic cells. Biochemical and Biophysical Research Communications328709720. doi:10.1016/j.bbrc.2004.11.072.

  • YeapBBChubbSAFlickerLMcCaulKAEbelingPRBeilbyJPNormanPE2010Reduced serum total osteocalcin is associated with metabolic syndrome in older men via waist circumference, hyperglycemia, and triglyceride levels. European Journal of Endocrinology163265272. doi:10.1530/EJE-10-0414.

  • YoshikawaYKodeAXuLMosialouISilvaBCFerronMClemensTLEconomidesANKousteniS2011Genetic evidence points to an osteocalcin-independent influence of osteoblasts on energy metabolism. Journal of Bone and Mineral Research2620122025. doi:10.1002/jbmr.417.

  • ZborowskiJVCauleyJATalbottEOGuzickDSWintersSJ2000Clinical review 116: bone mineral density, androgens, and the polycystic ovary: the complex and controversial issue of androgenic influence in female bone. Journal of Clinical Endocrinology and Metabolism8534963506. doi:10.1210/jc.85.10.3496.

If the inline PDF is not rendering correctly, you can download the PDF file here.

 

      Society for Endocrinology

Article Information

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 966 966 146
PDF Downloads 136 136 19

Altmetrics

Related Articles

Figures

  • View in gallery

    Gonads regulate bone physiology via the sex steroid hormones they produce. Testosterone and estrogen secreted by gonads are essential for the skeletal growth, maturation, and maintenance in both men and women. The sex steroid hormones regulate the apoptosis and/or proliferation of osteoblasts and/or osteoclasts.

  • View in gallery

    Bone via osteocalcin, an osteoblast-derived hormone, regulates testosterone production in testis. Following its binding to a GPRC6A expressed on Leydig cells of the testes, osteocalcin promotes in a cAMP-response element binding protein (CREB)-dependent manner testosterone production by testis. CREB binds to the promoter regions and activates the expression of several genes encoding for the enzymes that are necessary for testosterone biosynthesis, such as STAR, CYP11A, 3β-HSD, and CYP17. Steroidogenic acute regulatory protein (StAR) is crucial for transport of cholesterol to mitochondria where biosynthesis of steroids is initiated. CYP11A encodes the cholesterol side-chain cleavage enzyme (P450scc) that catalyzes the first and rate-limiting step, which converts cholesterol to pregnenolone. 3β-HSD and CYP17 encode two enzymes required during the conversion of pregnenolone to testosterone. Testosterone is a sex steroid hormone required for many aspects of testicular functions, such as germ cell survival and spermatogenesis.

References

AonumaHMiyakoshiNHongoMKasukawaYShimadaY2009Low serum levels of undercarboxylated osteocalcin in postmenopausal osteoporotic women receiving an inhibitor of bone resorption. Tohoku Journal of Experimental Medicine218201205. doi:10.1620/tjem.218.201.

AraujoABTravisonTGLederBZMcKinlayJB2008Correlations between serum testosterone, estradiol, and sex hormone-binding globulin and bone mineral density in a diverse sample of men. Journal of Clinical Endocrinology and Metabolism9321352141. doi:10.1210/jc.2007-1469.

van den BeldAWde JongFHGrobbeeDEPolsHALambertsSW2000Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men. Journal of Clinical Endocrinology and Metabolism8532763282. doi:10.1210/jc.85.9.3276.

BertelloniSBaroncelliGIBattiniRPerriGSaggeseG1995Short-term effect of testosterone treatment on reduced bone density in boys with constitutional delay of puberty. Journal of Bone and Mineral Research1014881495. doi:10.1002/jbmr.5650101009.

BodinePVRiggsBLSpelsbergTC1995Regulation of c-fos expression and TGF-β production by gonadal and adrenal androgens in normal human osteoblastic cells. Journal of Steroid Biochemistry and Molecular Biology52149158. doi:10.1016/0960-0760(94)00165-I.

BordSHornerABeavanSCompstonJ2001Estrogen receptors α and β are differentially expressed in developing human bone. Journal of Clinical Endocrinology and Metabolism8623092314. doi:10.1210/jc.86.5.2309.

BouillonRBexMVanderschuerenDBoonenS2004Estrogens are essential for male pubertal periosteal bone expansion. Journal of Clinical Endocrinology and Metabolism8960256029. doi:10.1210/jc.2004-0602.

BuchananJRMyersCLloydTLeuenbergerPDemersLM1988Determinants of peak trabecular bone density in women: the role of androgens, estrogen, and exercise. Journal of Bone and Mineral Research3673680. doi:10.1002/jbmr.5650030613.

CallewaertFVenkenKOphoffJDe GendtKTorcasioAvan LentheGHVan OosterwyckHBoonenSBouillonRVerhoevenG2009Differential regulation of bone and body composition in male mice with combined inactivation of androgen and estrogen receptor-α. FASEB Journal23232240. doi:10.1096/fj.08-113456.

CallewaertFBoonenSVanderschuerenD2010aSex steroids and the male skeleton: a tale of two hormones. Trends in Endocrinology and Metabolism218995. doi:10.1016/j.tem.2009.09.002.

CallewaertFSinnesaelMGielenEBoonenSVanderschuerenD2010bSkeletal sexual dimorphism: relative contribution of sex steroids, GH–IGF1, and mechanical loading. Journal of Endocrinology207127134. doi:10.1677/JOE-10-0209.

CallewaertFVenkenKKopchickJJTorcasioAvan LentheGHBoonenSVanderschuerenD2010cSexual dimorphism in cortical bone size and strength but not density is determined by independent and time-specific actions of sex steroids and IGF-1: evidence from pubertal mouse models. Journal of Bone and Mineral Research25617626. doi:10.1359/jbmr.090828.

ClarkeBLKhoslaS2010Physiology of bone loss. Radiologic Clinics of North America48483495. doi:10.1016/j.rcl.2010.02.014.

CouseJFKorachKS1999Estrogen receptor null mice: what have we learned and where will they lead us?Endocrine Reviews20358417. doi:10.1210/er.20.3.358.

CouseJFHewittSCBunchDOSarMWalkerVRDavisBJKorachKS1999Postnatal sex reversal of the ovaries in mice lacking estrogen receptors α and β. Science28623282331. doi:10.1126/science.286.5448.2328.

Fernandez-RealJMIzquierdoMOrtegaFGorostiagaEGomez-AmbrosiJMoreno-NavarreteJMFruhbeckGMartinezCIdoateFSalvadorJ2009The relationship of serum osteocalcin concentration to insulin secretion, sensitivity, and disposal with hypocaloric diet and resistance training. Journal of Clinical Endocrinology and Metabolism94237245. doi:10.1210/jc.2008-0270.

FerronMHinoiEKarsentyGDucyP2008Osteocalcin differentially regulates β cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. PNAS10552665270. doi:10.1073/pnas.0711119105.

FerronMWeiJYoshizawaTDel FattoreADePinhoRATetiADucyPKarsentyG2010Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell142296308. doi:10.1016/j.cell.2010.06.003.

FinkelsteinJSKlibanskiANeerRM1996A longitudinal evaluation of bone mineral density in adult men with histories of delayed puberty. Journal of Clinical Endocrinology and Metabolism8111521155. doi:10.1210/jc.81.3.1152.

FulzeleKRiddleRCDiGirolamoDJCaoXWanCChenDFaugereMCAjaSHussainMABruningJC2010Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell142309319. doi:10.1016/j.cell.2010.06.002.

GarneroPSornay-RenduEChapuyMCDelmasPD1996Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. Journal of Bone and Mineral Research11337349. doi:10.1002/jbmr.5650110307.

GillRKTurnerRTWronskiTJBellNH1998Orchiectomy markedly reduces the concentration of the three isoforms of transforming growth factor β in rat bone, and reduction is prevented by testosterone. Endocrinology139546550. doi:10.1210/en.139.2.546.

HinoiEGaoNJungDYYadavVYoshizawaTMyersMGJrChuaSCJrKimJKKaestnerKHKarsentyG2008The sympathetic tone mediates leptin's inhibition of insulin secretion by modulating osteocalcin bioactivity. Journal of Cell Biology18312351242. doi:10.1083/jcb.200809113.

HughesDEDaiATiffeeJCLiHHMundyGRBoyceBF1996Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-β. Nature Medicine211321136. doi:10.1038/nm1096-1132.

HwangYCJeongIKAhnKJChungHY2009The uncarboxylated form of osteocalcin is associated with improved glucose tolerance and enhanced β-cell function in middle-aged male subjects. Diabetes/Metabolism Research and Reviews25768772. doi:10.1002/dmrr.1045.

ImJAYuBPJeonJYKimSH2008Relationship between osteocalcin and glucose metabolism in postmenopausal women. Clinica Chimica Acta3966669. doi:10.1016/j.cca.2008.07.001.

ImaiYYounMYKondohSNakamuraTKouzmenkoAMatsumotoTTakadaITakaokaKKatoS2009Estrogens maintain bone mass by regulating expression of genes controlling function and life span in mature osteoclasts. Annals of the New York Academy of Sciences1173 (Suppl 1) E31E39. doi:10.1111/j.1749-6632.2009.04954.x.

JilkaRLHangocGGirasoleGPasseriGWilliamsDCAbramsJSBoyceBBroxmeyerHManolagasSC1992Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science2578891. doi:10.1126/science.1621100.

JimiEIkebeTTakahashiNHirataMSudaTKogaT1996Interleukin-1α activates an NF-kappaB-like factor in osteoclast-like cells. Journal of Biological Chemistry27146054608. doi:10.1074/jbc.271.9.4605.

KanazawaIYamaguchiTYamamotoMYamauchiMKuriokaSYanoSSugimotoT2009Serum osteocalcin level is associated with glucose metabolism and atherosclerosis parameters in type 2 diabetes mellitus. Journal of Clinical Endocrinology and Metabolism944549. doi:10.1210/jc.2008-1455.

KasperkCHWergedalJEFarleyJRLinkhartTATurnerRTBaylinkDJ1989Androgens directly stimulate proliferation of bone cells in vitro. Endocrinology12415761578. doi:10.1210/endo-124-3-1576.

KatznelsonLFinkelsteinJSSchoenfeldDARosenthalDIAndersonEJKlibanskiA1996Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. Journal of Clinical Endocrinology and Metabolism8143584365. doi:10.1210/jc.81.12.4358.

KaufmanJMVermeulenA2005The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocrine Reviews26833876. doi:10.1210/er.2004-0013.

KellyPJTwomeyLSambrookPNEismanJA1990Sex differences in peak adult bone mineral density. Journal of Bone and Mineral Research511691175. doi:10.1002/jbmr.5650051112.

KhoslaS2010aUpdate in male osteoporosis. Journal of Clinical Endocrinology and Metabolism95310. doi:10.1210/jc.2009-1740.

KhoslaS2010bUpdate on estrogens and the skeleton. Journal of Clinical Endocrinology and Metabolism9535693577. doi:10.1210/jc.2010-0856.

KhoslaSRiggsBL2005Pathophysiology of age-related bone loss and osteoporosis. Endocrinology and Metabolism Clinics of North America3410151030 xi. doi:10.1016/j.ecl.2005.07.009.

KhoslaSMeltonLJIIIAtkinsonEJO'FallonWM2001Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. Journal of Clinical Endocrinology and Metabolism8635553561. doi:10.1210/jc.86.8.3555.

KindblomJMOhlssonCLjunggrenOKarlssonMKTivestenASmithUMellstromD2009Plasma osteocalcin is inversely related to fat mass and plasma glucose in elderly Swedish men. Journal of Bone and Mineral Research24785791. doi:10.1359/jbmr.081234.

KirmaniSChristenDvan LentheGHFischerPRBouxseinMLMcCreadyLKMeltonLJIIIRiggsBLAminSMullerR2009Bone structure at the distal radius during adolescent growth. Journal of Bone and Mineral Research2410331042. doi:10.1359/jbmr.081255.

KousteniSBellidoTPlotkinLIO'BrienCABodennerDLHanLHanKDiGregorioGBKatzenellenbogenJAKatzenellenbogenBS2001Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell104719730.

KousteniSChenJRBellidoTHanLAliAAO'BrienCAPlotkinLFuQMancinoATWenY2002Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science298843846. doi:10.1126/science.1074935.

KrumSAMiranda-CarboniGAHauschkaPVCarrollJSLaneTFFreedmanLPBrownM2008Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival. EMBO Journal27535545. doi:10.1038/sj.emboj.7601984.

KuangDYaoYLamJTsushimaRGHampsonDR2005Cloning and characterization of a family C orphan G-protein coupled receptor. Journal of Neurochemistry93383391. doi:10.1111/j.1471-4159.2005.03025.x.

LederBZRohrerJLRubinSDGalloJLongcopeC2004Effects of aromatase inhibition in elderly men with low or borderline-low serum testosterone levels. Journal of Clinical Endocrinology and Metabolism8911741180. doi:10.1210/jc.2003-031467.

LeeNKSowaHHinoiEFerronMAhnJDConfavreuxCDacquinRMeePJMcKeeMDJungDY2007Endocrine regulation of energy metabolism by the skeleton. Cell130456469. doi:10.1016/j.cell.2007.05.047.

LevingerIZebazeRJerumsGHareDLSeligSSeemanE2011The effect of acute exercise on undercarboxylated osteocalcin in obese men. Osteoporosis International2216211626. doi:10.1007/s00198-010-1370-7.

LindbergMKAlataloSLHalleenJMMohanSGustafssonJAOhlssonC2001Estrogen receptor specificity in the regulation of the skeleton in female mice. Journal of Endocrinology171229236. doi:10.1677/joe.0.1710229.

LindsayRHartDMAitkenJMMacDonaldEBAndersonJBClarkeAC1976Long-term prevention of postmenopausal osteoporosis by oestrogen. Evidence for an increased bone mass after delayed onset of oestrogen treatment. Lancet110381041. doi:10.1016/S0140-6736(76)92217-0.

LindsayRHartDMForrestCBairdC1980Prevention of spinal osteoporosis in oophorectomised women. Lancet211511154. doi:10.1016/S0140-6736(80)92592-1.

LupuFTerwilligerJDLeeKSegreGVEfstratiadisA2001Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. Developmental Biology229141162. doi:10.1006/dbio.2000.9975.

ManolagasSCKousteniSJilkaRL2002Sex steroids and bone. Recent Progress in Hormone Research57385409. doi:10.1210/rp.57.1.385.

MellstromDJohnellOLjunggrenOErikssonALLorentzonMMallminHHolmbergARedlund-JohnellIOrwollEOhlssonC2006Free testosterone is an independent predictor of BMD and prevalent fractures in elderly men: MrOS Sweden. Journal of Bone and Mineral Research21529535. doi:10.1359/jbmr.060110.

MichaelHHarkonenPLVaananenHKHentunenTA2005Estrogen and testosterone use different cellular pathways to inhibit osteoclastogenesis and bone resorption. Journal of Bone and Mineral Research2022242232. doi:10.1359/JBMR.050803.

NakamuraTImaiYMatsumotoTSatoSTakeuchiKIgarashiKHaradaYAzumaYKrustAYamamotoY2007Estrogen prevents bone loss via estrogen receptor α and induction of Fas ligand in osteoclasts. Cell130811823. doi:10.1016/j.cell.2007.07.025.

NobleBRoutledgeJStevensHHughesIJacobsonW1999Androgen receptors in bone-forming tissue. Hormone Research513136. doi:10.1159/000023310.

OuryFSumaraGSumaraOFerronMChangHSmithCEHermoLSuarezSRothBLDucyP2011Endocrine regulation of male fertility by the skeleton. Cell144796809. doi:10.1016/j.cell.2011.02.004.

OzOKZerwekhJEFisherCGravesKNanuLMillsapsRSimpsonER2000Bone has a sexually dimorphic response to aromatase deficiency. Journal of Bone and Mineral Research15507514. doi:10.1359/jbmr.2000.15.3.507.

PacificiR1996Estrogen, cytokines, and pathogenesis of postmenopausal osteoporosis. Journal of Bone and Mineral Research1110431051. doi:10.1002/jbmr.5650110802.

PiMFaberPEkemaGJacksonPDTingAWangNFontilla-PooleMMaysRWBrundenKRHarringtonJJ2005Identification of a novel extracellular cation-sensing G-protein-coupled receptor. Journal of Biological Chemistry2804020140209.

PiMChenLHuangMZZhuWRinghoferBLuoJChristensonLLiBZhangJJacksonPD2008GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome. PLoS ONE3e3858doi:10.1371/journal.pone.0003858.

PiMZhangLLeiSFHuangMZZhuWZhangJShenHDengHWQuarlesLD2010Impaired osteoblast function in GPRC6A null mice. Journal of Bone and Mineral Research2510921102.

PiMWuYQuarlesLD2011GPRC6A mediates responses to osteocalcin in β-cells in vitro and pancreas in vivo. Journal of Bone and Mineral Research2616801683. doi:10.1002/jbmr.390.

PincusG1962Reproduction. Annual Review of Physiology245784. doi:10.1146/annurev.ph.24.030162.000421.

PittasAGHarrisSSEliadesMStarkPDawson-HughesB2009Association between serum osteocalcin and markers of metabolic phenotype. Journal of Clinical Endocrinology and Metabolism94827832. doi:10.1210/jc.2008-1422.

RachedMTKodeAXuLYoshikawaYPaikJHDepinhoRAKousteniS2010FoxO1 is a positive regulator of bone formation by favoring protein synthesis and resistance to oxidative stress in osteoblasts. Cell Metabolism11147160. doi:10.1016/j.cmet.2010.01.001.

RiggsBLO'FallonWMMuhsJO'ConnorMKKumarRMeltonLJIII1998Long-term effects of calcium supplementation on serum parathyroid hormone level, bone turnover, and bone loss in elderly women. Journal of Bone and Mineral Research13168174. doi:10.1359/jbmr.1998.13.2.168.

RiggsBLKhoslaSMeltonLJIII2002Sex steroids and the construction and conservation of the adult skeleton. Endocrine Reviews23279302. doi:10.1210/er.23.3.279.

RochiraVZirilliLMadeoBArandaCCaffagniGFabreBMontangeroVERoldanEJMaffeiLCaraniC2007Skeletal effects of long-term estrogen and testosterone replacement treatment in a man with congenital aromatase deficiency: evidences of a priming effect of estrogen for sex steroids action on bone. Bone4016621668. doi:10.1016/j.bone.2007.01.022.

SchnorrJABrayMJVeldhuisJD2001Aromatization mediates testosterone's short-term feedback restraint of 24-hour endogenously driven and acute exogenous gonadotropin-releasing hormone-stimulated luteinizing hormone and follicle-stimulating hormone secretion in young men. Journal of Clinical Endocrinology and Metabolism8626002606. doi:10.1210/jc.86.6.2600.

SeemanE2001Clinical review 137: sexual dimorphism in skeletal size, density, and strength. Journal of Clinical Endocrinology and Metabolism8645764584. doi:10.1210/jc.86.10.4576.

StepanJJLachmanMZverinaJPacovskyVBaylinkDJ1989Castrated men exhibit bone loss: effect of calcitonin treatment on biochemical indices of bone remodeling. Journal of Clinical Endocrinology and Metabolism69523527. doi:10.1210/jcem-69-3-523.

StevensonJCCustMPGangarKFHillardTCLeesBWhiteheadMI1990Effects of transdermal versus oral hormone replacement therapy on bone density in spine and proximal femur in postmenopausal women. Lancet336265269. doi:10.1016/0140-6736(90)91801-G.

TauKRHefferanTEWatersKMRobinsonJASubramaniamMRiggsBLSpelsbergTC1998Estrogen regulation of a transforming growth factor-β inducible early gene that inhibits deoxyribonucleic acid synthesis in human osteoblasts. Endocrinology13913461353. doi:10.1210/en.139.3.1346.

T'SjoenGGGiagulliVADelvaHCrabbePDe BacquerDKaufmanJM2005Comparative assessment in young and elderly men of the gonadotropin response to aromatase inhibition. Journal of Clinical Endocrinology and Metabolism9057175722. doi:10.1210/jc.2005-0982.

VandenputLOhlssonC2009Estrogens as regulators of bone health in men. Nature Reviews. Endocrinology5437443. doi:10.1038/nrendo.2009.112.

VanderschuerenDVandenputLBoonenSLindbergMKBouillonROhlssonC2004Androgens and bone. Endocrine Reviews25389425. doi:10.1210/er.2003-0003.

VenkenKSchuitFVan LommelLTsukamotoKKopchickJJCoschiganoKOhlssonCMoverareSBoonenSBouillonR2005Growth without growth hormone receptor: estradiol is a major growth hormone-independent regulator of hepatic IGF-I synthesis. Journal of Bone and Mineral Research2021382149. doi:10.1359/JBMR.050811.

VenkenKDe GendtKBoonenSOphoffJBouillonRSwinnenJVVerhoevenGVanderschuerenD2006Relative impact of androgen and estrogen receptor activation in the effects of androgens on trabecular and cortical bone in growing male mice: a study in the androgen receptor knockout mouse model. Journal of Bone and Mineral Research21576585. doi:10.1359/jbmr.060103.

VenkenKCallewaertFBoonenSVanderschuerenD2008Sex hormones, their receptors and bone health. Osteoporosis International1915171525. doi:10.1007/s00198-008-0609-z.

VidalOKindblomLGOhlssonC1999Expression and localization of estrogen receptor-β in murine and human bone. Journal of Bone and Mineral Research14923929. doi:10.1359/jbmr.1999.14.6.923.

VidalOLindbergMKHollbergKBaylinkDJAnderssonGLubahnDBMohanSGustafssonJAOhlssonC2000Estrogen receptor specificity in the regulation of skeletal growth and maturation in male mice. PNAS9754745479. doi:10.1073/pnas.97.10.5474.

WeiSJonesGThomsonROtahalPDwyerTVennA2010Menstrual irregularity and bone mass in premenopausal women: cross-sectional associations with testosterone and SHBG. BMC Musculoskeletal Disorders11288doi:10.1186/1471-2474-11-288.

WellendorphPBrauner-OsborneH2004Molecular cloning, expression, and sequence analysis of GPRC6A, a novel family C G-protein-coupled receptor. Gene3353746. doi:10.1016/j.gene.2004.03.003.

WellendorphPJohansenLDJensenAACasanovaEGassmannMDeprezPClement-LacroixPBettlerBBrauner-OsborneH2009No evidence for a bone phenotype in GPRC6A knockout mice under normal physiological conditions. Journal of Molecular Endocrinology42215223. doi:10.1677/JME-08-0149.

WinhoferYHandisuryaATuraABittighoferCKleinKSchneiderBBieglmayerCWagnerOFPaciniGLugerA2010Osteocalcin is related to enhanced insulin secretion in gestational diabetes mellitus. Diabetes Care33139143. doi:10.2337/dc09-1237.

XingLBoyceBF2005Regulation of apoptosis in osteoclasts and osteoblastic cells. Biochemical and Biophysical Research Communications328709720. doi:10.1016/j.bbrc.2004.11.072.

YeapBBChubbSAFlickerLMcCaulKAEbelingPRBeilbyJPNormanPE2010Reduced serum total osteocalcin is associated with metabolic syndrome in older men via waist circumference, hyperglycemia, and triglyceride levels. European Journal of Endocrinology163265272. doi:10.1530/EJE-10-0414.

YoshikawaYKodeAXuLMosialouISilvaBCFerronMClemensTLEconomidesANKousteniS2011Genetic evidence points to an osteocalcin-independent influence of osteoblasts on energy metabolism. Journal of Bone and Mineral Research2620122025. doi:10.1002/jbmr.417.

ZborowskiJVCauleyJATalbottEOGuzickDSWintersSJ2000Clinical review 116: bone mineral density, androgens, and the polycystic ovary: the complex and controversial issue of androgenic influence in female bone. Journal of Clinical Endocrinology and Metabolism8534963506. doi:10.1210/jc.85.10.3496.

Cited By

PubMed

Google Scholar