Broadening the role of osteocalcin in the hypothalamic-pituitary-gonadal axis

in Journal of Endocrinology
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  • 1 Department of Endocrinology and Metabolism, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

Correspondence should be addressed to W Liu: sue_liuwei@163.com

Bone is emerging as a versatile endocrine organ and its interactions with apparently unrelated organs are being more widely recognized. Osteocalcin (OCN), a polypeptide hormone secreted by osteoblasts, has been found to exert multiple endocrine functions through its metabolically active form, uncarboxylated OCN (uOCN). Mounting evidence has shown that following its binding to G-protein coupled receptor 6a (Gprc6a) in the peripheral tissues, uOCN acts on pancreatic β cells to increase insulin secretion, and on muscle and white adipose tissue to promote glucose and lipid metabolism. More strikingly, researchers have found a surprising role of uOCN in testicular function to facilitating testosterone biosynthesis and regulating male fertility via a pancreas-bone-gonadal axis. However, the detailed functional mechanisms of uOCN on the hypothalamic–pituitary–gonadal axis or the pancreas–bone–gonadal axis are not fully understood. Besides highlighting the regulatory mechanisms of uOCN in the hypothalamus and pituitary, we also discuss its role in male as well as female fertility and its potential clinical implications in some reproductive endocrine diseases and pubertal developmental disorders.

Abstract

Bone is emerging as a versatile endocrine organ and its interactions with apparently unrelated organs are being more widely recognized. Osteocalcin (OCN), a polypeptide hormone secreted by osteoblasts, has been found to exert multiple endocrine functions through its metabolically active form, uncarboxylated OCN (uOCN). Mounting evidence has shown that following its binding to G-protein coupled receptor 6a (Gprc6a) in the peripheral tissues, uOCN acts on pancreatic β cells to increase insulin secretion, and on muscle and white adipose tissue to promote glucose and lipid metabolism. More strikingly, researchers have found a surprising role of uOCN in testicular function to facilitating testosterone biosynthesis and regulating male fertility via a pancreas-bone-gonadal axis. However, the detailed functional mechanisms of uOCN on the hypothalamic–pituitary–gonadal axis or the pancreas–bone–gonadal axis are not fully understood. Besides highlighting the regulatory mechanisms of uOCN in the hypothalamus and pituitary, we also discuss its role in male as well as female fertility and its potential clinical implications in some reproductive endocrine diseases and pubertal developmental disorders.

Brief introduction on osteocalcin (OCN)

Bone, at earlier times, had mostly been regarded as a static and isolated organ believed to provide only structural support to the body (Elefteriou et al. 2014). However, more interesting discoveries in the last two decades have revealed a novel function of bone as an endocrine organ. These findings have revealed surprising interactions of bone with apparently unrelated organs, including the pancreas, adipose tissue, muscle, testes and even the central nervous system (CNS). Endocrine functions of bone were first identified when it was found to regulate energy metabolism through the action of osteocalcin (OCN), a polypeptide hormone exclusively secreted by bone-forming osteoblasts (Lee et al. 2007, Dirckx et al. 2019). OCN contains three gamma-carboxyglutamic acid (Gla) motifs, which are carboxylated by a vitamin-K-dependent γ-glutamyl carboxylase (GGCX) through a posttranslational modification, leading to conformational changes that stabilize the α-helix motif of the protein and confer a greater affinity for Ca2+ and hydroxyapatite (Lee et al. 2000). Therefore, carboxylated OCN is thought to be a constitutive protein of the bone matrix and is considered a marker of bone formation and remodeling (Razzaque 2011, Li et al. 2016, Shan et al. 2019). However, since the discovery of novel functions of this protein in its metabolically active form, uncarboxylated OCN (uOCN), the notion of OCN serving as a marker only has warranted reconsideration. Due to decarboxylation or low activity of GGCX, some OCN is partially carboxylated and cannot readily bind to hydroxyapatite because of the unstructured random coil, leading to its leakage into the blood (Bisby 1980).

After its release into systemic circulation, uOCN exerts multiple endocrine functions through a peripheral receptor called the G-protein coupled receptor 6a (Gprc6a) (Oury et al. 2013a, Wei et al. 2014, Mera et al. 2016, Liu et al. 2018) and another receptor called the G-protein coupled receptor 158 (Gpr158) in the CNS (Oury et al. 2013b, Khrimian et al. 2017b, Guo et al. 2018, Kosmidis et al. 2018). On one hand, uOCN binds with Gprc6a in the pancreas, intestine, adipose tissue, male gonads and muscle to promote cell proliferation, stimulate insulin secretion, improve insulin sensitivity (Lee et al. 2007, Ferron et al. 2012), regulate male fertility (Oury et al. 2011, 2013a, 2015) and muscle power (Mera et al. 2016); on the other hand, it passes through the blood-brain barrier (BBB) and accumulates in the brainstem, thalamus and hypothalamus (Oury et al. 2013b), where it binds with Gpr158 in specific neurons to influence various neurotransmitter syntheses and signaling (Khrimian et al. 2017b, Kosmidis et al. 2018), thus playing a crucial role in brain development, cognitive function and motor coordination (Khrimian et al. 2017a,b, Guo et al. 2018, Glatigny et al. 2019, Shan et al. 2019). More recently, a role of OCN has also been reported in acute stress response (Berger et al. 2019), broadening the role of the skeletal system in a wider array of physiological responses; implying that the bone is an endocrine system of intrinsic nature in which OCN is a key driving component of its endocrine functions.

Male fertility and osteocalcin: regulatory functions of osteocalcin in the testes

The first line of research suggesting a role of bone in testicular function dates back to 2011, led by the Karsenty group (Oury et al. 2011). Using co-culture assays, they found that the supernatant of osteoblast cultures, but not mesenchymal cell cultures, augments testosterone production by Leydig cells over four-fold while also increasing testosterone secretion from testes explants over three-fold. Based on their previous observations that OCN-deficient male mice (OCN−/−) bred poorly, they hypothesized that OCN secretion by osteoblasts may be a key factor for the regulation of male fertility. Later studies involving in vivo models found that both global OCN−/− and osteoblast-specific OCN-deficient (OCNosb−/−) male mice exhibit lower levels of circulating testosterone, decreased testis size and weight, reduced number of spermatocytes and increased germ cell apoptosis compared with their WT littermates. Interestingly, similar to changes associated with primary testicular failure, the circulating levels of luteinizing hormone (LH) are also increased in OCN−/− mice, possibly due to a loss of negative feedback in the absence of OCN (Oury et al. 2011). More interestingly, compared with the OCN−/− mice, these parameters are found to be opposite in male Esp−/− mice (Oury et al. 2011). Esp−/− mice generally represent the opposite of OCN−/− mice, that is, while OCN−/− represents loss-of-function, Esp−/− represents gain-of-function of OCN in these mice (Oury et al. 2011). Esp encodes the osteotesticular protein tyrosine phosphatase (OST-PTP) to regulate the carboxylation of OCN (Ferron et al. 2010), thus Esp−/− mice produce more uOCN and have increased functional outputs of OCN (Fulzele et al. 2010). Therefore, the contrasting phenotypes of Esp−/− mice compared to OCN−/− mice suggest a crucial role for uOCN in the regulation of testicular health and function (Oury et al. 2011). It should be noted, however, that a homolog for the Esp gene has so not been identified in humans yet, raising a possibility for other genes and/or mechanisms in the regulation of OCN function in humans (Fulzele et al. 2010).

Then comes the question of which receptor mediates the functions of OCN. Taking advantage of the following facts, (I) uOCN induces cAMP production only but not tyrosine phosphorylation, ERK activation or intracellular calcium accumulation in Leydig cells, which indicates that its receptor might be a G-protein coupled receptor (GPCR); (II) while 22 out of 103 orphan GPCRs are predominantly expressed in testes, 4 out of them are enriched in Leydig cells and Gprc6a is found to be one of those 4 receptors; (III) Gprc6a−/− in all cells mimics the metabolic and fertile phenotypes similar to that of OCN−/− mice (Pi et al. 2008), thus, Gprc6a is identified as the receptor to transduce OCN signaling in Leydig cells. After binding to Gprc6a in Leydig cells, OCN induces cAMP response element-binding protein (CREB) phosphorylation to regulate testosterone biosynthesis by regulating the expression of key enzymes involved in this biosynthetic pathway (Oury et al. 2011).

An association of uOCN with vitamin D has been reported in the context of male fertility as well. Vitamin D, or more precisely its active form – 1,25(OH)2D3, is important for Leydig cell function and testosterone release while 1,25(OH)2D3 deficiency is associated with lower testosterone/estradiol ratio in young men (Holt et al. 2020). Utilizing a Leydig cell line, De Toni and colleagues found that after binding with Gprc6a, uOCN regulates the expression of Cyp2r, which encodes for the enzyme microsomal vitamin D 25-hydroxylase necessary for the conversion of vitamin D to 1,25(OH)2D3 (De Toni et al. 2014), suggesting that the beneficial roles of uOCN on testicular function may be at least partially mediated by regulating the vitamin D regulatory pathways, thus adding another dimension to the role of uOCN in testes (Karsenty 2014).

Besides, Oury and colleagues found the phenomenon that despite having reduced sperm numbers, OCN−/− male mice also produce fewer litters (Oury et al. 2011). One plausible explanation may be that OCN may also influence fertility through testosterone’s modulation of sexual behavior in the brain and alteration of general reproductive and metabolic hormone profiles, thus resulting in reduced mating behavior in these mice (Schuh-Huerta & Pera 2011).

All the above evidence indicates that male mice lacking OCN, or its receptor, seem to represent a model for aging males, who are characterized by decreased bone mass, decreased testosterone levels, lower sperm counts, and sexual dysfunction. Particularly, this can be supported by the fact that OCN and its receptor, as well as other components of the signaling pathway, are present in the human testes (Schuh-Huerta & Pera 2011). Indeed, series of cross-sectional and longitudinal studies have explored the potential andrological implications of OCN in humans. In a clinical survey, total serum OCN was found to be positively associated with total testosterone (TT) and free testosterone (FT) in 2400 men aged 20–69 years, especially in men with central obesity (Liao et al. 2013). Besides, multiple regression analysis of 69 males with type 2 diabetes indicated that uOCN and uOCN% are positively associated with FT independent of age, duration of diabetes and BMI (Kanazawa et al. 2013). Khosla and colleagues recently showed that there is a significant association between serum OCN and testosterone levels during mid-puberty in males (Kirmani et al. 2011). Moreover, although there was no evidence found that uOCN modulates circulating testosterone in the study of Yeap and colleagues which included 2966 older men aged 70–89 years in Australia, its inverse correlation with estradiol also indicates the relationship of uOCN with overall sex hormone status (Yeap et al. 2015). All these clinical findings with consolidated molecular evidence from cell/animal studies lay the foundation for a strong correlation between OCN and male reproduction, expanding the physiological repertoire of OCN in male testicular function.

Does OCN influence the traditional hypothalamic–pituitary–gonadal axis for its effect on male fertility?

Although there is evidence suggesting a direct role for OCN in the testes, there are few studies focusing on whether OCN has a direct effect on the upstream targets of the hypothalamic–pituitary–gonadal (HPG) axis. The hypothalamus is an integral part of the CNS regulating neuroendocrine functions mainly through its activity on the anterior pituitary and on the autonomic nervous system. Recently, the direct regulatory functions of OCN via its receptors in the CNS has been explored, including its beneficial role in normal brain development (Oury et al. 2013b), or in pathological conditions such as cognitive dysfunction (Khrimian et al. 2017b) and Parkinson’s-related motor deficits (Guo et al. 2018). Findings from animal studies on OCN’s regulation of reproduction and the CNS are summarized in Table 1. However, whether it may have any effect on the hypothalamus and thereby regulating the HPG axis remains unclear.

Researches in animals and their findings focused on OCN’s regulation of reproduction and nervous system.

AuthorYearJournalSpeciesFindings
OCN and reproductionOury et al. 20112011CellMouseBy binding to Gprc6a expressed in the Leydig cells of the testes, OCN regulates in a CREB-dependent manner the expression of enzymes required for testosterone synthesis, promoting germ cell survival.
Oury et al. 2013a2013The Journal of Clinical InvestigationMouseOCN and LH act in 2 parallel pathways and OCN-stimulated testosterone synthesis is positively regulated by bone resorption and insulin signaling in osteoblasts.
Li and Li 20142014Hormone and Metabolic ResearchMouseOCN injection promotes growth in mice and increases testosterone in testes and serum. Besides, it induces GH expression in pituitary and GHR and IGF-1 expression in liver. OCN, endocrine steroids, and the GH/IGF-1 axis comprise a system that controls growth physiology and reproductive endocrinology.
De Toni et al. 20162016EndocrinologyHEK-293 cellsSimilar structural moieties exist between uOCN and SHBG that are predicted to bind to Gprc6a. Unliganded SHBG specifically bound the membrane of HEK-293 cells transfected with Gprc6a and was displaced by uOCN at 100-fold molar excess. Furthermore, Erk1/2 phosphorylation after stimulation of Gprc6a with uOCN was significantly blunted by 100-fold molar excess of unliganded SHBG.
Diegel et al. 20202020PLoS GeneticsMouseMice with a new Bglap and Bglap2 double-knockout allele (Bglap/2p.Pro25fs17Ter) that was generated by CRISPR/Cas9-mediated gene editing did not have significant differences from WT littermates in serum glucose levels and male fertility.
OCN and nervous systemOury et al. 2013b2013CellMouseOCN crosses the blood-brain barrier, binds to neurons of the brainstem, midbrain and hippocampus, enhances the synthesis of monoamine neurotransmitters, inhibits GABA synthesis, prevents anxiety and depression and favors learning and memory. Maternal OCN crosses the placenta during pregnancy and prevents neuronal apoptosis before embryos synthesize this hormone.
Khrimian et al. 2017b2017Journal of Experimental MedicineMouseGpr158 expressed in neurons of the CA3 region of the hippocampus transduces OCN’s regulation of hippocampal-dependent memory in part through IP3 and BDNF.
Khrimian et al. 2017a2017Molecular MetabolismMouseRunx2+/- mice had reduced circulating levels of bioactive OCN, and reduced expression of OCN’s target genes in the brain. Consequently, they had significant impairment in cognitive function and increased anxiety-like behavior.
Kosmidis et al. 20182018Cell ReportsMouseRbAp48, a molecular determinant of age-related memory loss, controls the expression of BDNF and Gpr158, both critical components of OCN signaling in the mouse hippocampus. RbAp48 upregulation via OCN signaling ameliorates age-related memory loss.
Guo et al. 20182018Frontiers in Molecular NeuroscienceRatOCN improves the behavioral dysfunction in PD rat models and reduces the tyrosine hydroxylase loss in the nigrostriatal system through the AKT/GSK3β signaling pathway.
Glatigny et al. 20192019Current BiologyMouseSystemic administration of young plasma into aged mice rejuvenates memory in an autophagy-dependent manner. Among these youthful factors, OCN is identified as a direct hormonal inducer of hippocampal autophagy.
Berger et al. 20192019Cell MetabolismMouseOCN permits manifestations of the acute stress response to unfold by signaling in post-synaptic parasympathetic neurons to inhibit their activity, thereby leaving the sympathetic tone unopposed.

AKT, Protein kinase B; BDNF, brain-derived neurotrophic factor; CA3, Cornu Ammonis 3; CREB, cyclic AMP response element-binding protein; Erk, extracellular regulated protein kinase; GABA, γ-aminobutyric acid; GH, growth hormone; Gpr158, G-protein coupled receptor 158; Gprc6a, G-protein coupled receptor 6a; GSK, glycogen synthase; IGF-1, insulin-like growth factor-1; IP3, inositol triphosphate; LH, luteinizing hormone; OCN, osteocalcin; PD, Parkinson’s disease; RbAp48, retinoblastoma-associated protein 48; Runx2, Runt-related transcription factor 2; SHBG, sex hormone-binding globulin; uOCN, uncarboxylated osteocalcin.

Supporting reasons for OCN’s regulation on hypothalamic-pituitary function are as follows: first, Gprc6a has been observed to be expressed in not only the testes and sertoli cells, but also in the hypothalamus and the anterior pituitary (Kuang et al. 2005, Pi et al. 2005, 2008, Pi & Quarles 2012). Moreover, the central OCN receptor Gpr158 is also known to be expressed in the hypothalamus and the pituitary in significant amounts (Piaggi et al. 2017). However, whether such expressions are exclusive to luteinizing hormone-releasing hormone (LHRH)-positive neurons or gonadotrophic pituitary cells is not clear. Moreover, there is no direct evidence that Gpr158 may have a role in the regulation of male fertility; whether Gpr158-null mice may have a deficit in male or female fertility should be a topic of further interest. Finding these answers will help to understand the precise mechanisms of OCN’s regulation of the hypothalamus or the pituitary. Secondly, leptin, which is known to be a major regulator of energy balance through its actions on the hypothalamus, has been shown to mediate its beneficial effects on energy homeostasis and on the bones by promoting circulatory OCN levels by involving receptors exclusively resident in the hypothalamus (Kalra et al. 2009). Moreover, it is suggested that leptin target sites involved in energy homeostasis are a part of the substrate network that also modulates OCN secretion from osteoblasts (Kalra et al. 2009), providing a possible basis for physiological actions of OCN on the hypothalamic regulatory proteins. Thirdly, a loss-of-function mutation of the OCN receptor in human was reported to be associated with hypergonadotropic hypogonadism, suggesting that OCN may be necessary for normal pituitary-gonadal axis function (Oury et al. 2013a). Interestingly, LH, which is produced in the pituitary glands, has been found to be correlated with OCN. Although there has been no solid consensus reached on the relation between LH and OCN, data from the Longitudinal Aging Study Amsterdam (LASA), an ongoing cohort study with a representative sample of the older Dutch population (65–88 years), suggest that serum OCN is positively correlated with LH levels (Limonard et al. 2015). However, observations from an animal study suggest otherwise. This study showed that neither OCN level is affected in LH-deficient (Lhb−/−) male mice nor is LH level affected in OCN−/− mice compared to their WT controls, suggesting the effects of OCN or LH on male reproduction are independent of each other (Oury et al. 2013a). The study further identified that OCN may rather regulate male reproduction through a different mechanism relating to bone resorption, in which it uses insulin as its upstream target to regulate male fertility, suggesting the existence of a pancreas-bone-testis axis in the control of male fertility that acts in parallel to the hypothalamus-pituitary-testis axis (Oury et al. 2013a).

From another mechanistic point of view, OCN’s possible role on the HPG axis may be supported by linking GABA activity and gonadotrophin-releasing hormone (GnRH), which is synthesized and released from GnRH neurons within the hypothalamus and regulates the secretion of LH. GABA content is found to be increased in all brain regions of OCN−/− mice, which is related to the increased expression of the key GABA synthesis enzymes Gad1 and Gad2. Meanwhile in the brain stem, OCN inhibits the action potential frequency of GABAergic intermediate neurons (Oury et al. 2013b). Although GABA is considered to be an inhibitory neurotransmitter in the adult brain, consensus has been reached that GABA activates adult GnRH neurons through GABAA receptors (Herbison & Moenter 2011, Moore et al. 2015). Therefore, there may be a possible role of OCN in regulating GnRH pulse frequency by regulating the GABAergic intermediate neurons. Figure 1 summarizes the possible regulatory mechanisms of OCN on the HPG axis.

Figure 1
Figure 1

Possible regulations of OCN on hypothalamic–pituitary–testis axis. OCN can pass through the blood-brain barrier and then bind to the hypothalamus and pituitary. By possible regulations on GnRH neurons and GABAergic neurons (Herbison & Moenter 2011), OCN may modulate the GnRH/LH pulse frequency, thus playing a role in regulating the LH amplitude and then the functions of testis. Previous studies have shown that following its binding to Gprc6a in Leydig cells, OCN can favor cAMP production that leads to the activation of the transcription factor CREB (cAMP response element binding). CREB activates the expression of several genes encoding the enzymes that are necessary for testosterone biosynthesis, such as StAR, Cyp11a, 3b-HSD and Cyp17 (Oury et al. 2011).

Citation: Journal of Endocrinology 249, 2; 10.1530/JOE-20-0203

Although some evidence supports the idea that OCN may play a role in the regulation of the HPG axis, or at least have a correlation with the components of this axis, there is also controversy where it has been shown that OCN actually may regulate the pancreas–bone–testis axis rather than the HPG axis to control male fertility. Nevertheless, evidence supporting either of these notions is very scarce, and therefore more work would be needed to understand the regulatory mechanisms of OCN on male fertility.

Is there any possibility of OCN playing a role in female fertility?

To date, the endocrine regulation of reproduction by OCN has been reported to be restricted to male reproduction only. Karsenty et al. reported that osteoblasts neither induce testosterone or estrogen production from ovaries in co-culture assays, nor affect female fertility, ovary weight, uterus morphology, follicles number or circulating levels of sex steroid hormones in OCN−/− female mice (Oury et al. 2011). Does this imply that OCN has no role in the regulation of female reproduction? Although currently there is insufficient evidence to support the idea that OCN may have a role in regulating female fertility, there are still some possibilities for such. In addition to the possible effects of OCN on hypothalamic–pituitary functions (as discussed above) to provide a basis for OCN regulation of female fertility, it is interesting that Gprc6a may regulate the aromatization of androgens to estrogen (Pi & Quarles 2012), thereby regulating the circulating estrogen levels in female mice. Moreover, a recent study demonstrated that serum OCN level is associated with an increase of bone age and peak LH in 206 girls with central precocious puberty, which indicates serum OCN may be associated with the onset of puberty in females (Lee et al. 2018). Further studies are warranted for exploring the regulation and precise mechanisms of OCN in female reproduction.

Clinical perspectives

PCOS is characterized by hyperandrogenism: is there a role for OCN signaling?

Polycystic ovary syndrome (PCOS), a complex metabolic and reproductive disease, is regarded as the most common endocrine disorder in women of reproductive age with a prevalence of 5–15% (Rosenfield & Ehrmann 2016). It is characterized by ovulatory dysfunction, polycystic ovaries, biochemical and/or clinical hyperandrogenism (Ehrmann 2005). In view of the beneficial functions of OCN in regulating both energy metabolism and reproduction, the question arises whether OCN might modulate risk of PCOS. Although Tapanainen and colleagues have reported that serum level of OCN is decreased in women with PCOS compared to healthy controls (Lingaiah et al. 2017), there has been no solid consensus reached to date on the effect of PCOS on serum OCN levels, especially the level of uOCN. Moreover, whether the alteration of OCN level is a cause of PCOS or is a result is more difficult to determine at present, warranting for more understanding of the crosstalk between OCN and PCOS.

To clarify the relation between uOCN and PCOS, the following four attributes are needed to be identified: (I) what is the serum level of uOCN in clinical patients or rodent models with PCOS compared to their controls? Circulating uOCN may not only directly act on the hypothalamus and pituitary to regulate LH release (Pi et al. 2010, Pi & Quarles 2012), in response to which androgens are secreted by the theca cells (Rosenfield & Ehrmann 2016), but also may affect the binding of Gprc6a with sex hormone-binding globulin (SHBG) (De Toni et al. 2016, 2019), thus leading to the alteration of the circulating testosterone level. In another study using a computational modeling, De Toni and colleagues found similar structural moieties between uOCN and SHBG. They found that unliganded-SHBG specifically binds to the membrane of HEK-293 cells transfected with Gprc6a (De Toni et al. 2019) and is displaced by uOCN when co-incubated at 100-fold molar excess (De Toni et al. 2016). Furthermore, specific downstream Erk1/2 phosphorylation following stimulation of Gprc6a with uOCN is significantly blunted by 100-fold molar excess of unliganded SHBG (De Toni et al. 2016). These data hint at a possible correlation between OCN and PCOS, and the first step to determine this would be to check the serum uOCN level in PCOS clinical patients or animal models against their controls. (II) If there is indeed an alteration of serum uOCN level in patients with PCOS, is this a cause for PCOS development or just a secondary biological change due to PCOS? This is an exceedingly difficult question to answer. To date, it is well-known that gonadal hormones have direct effects on bone metabolism. As PCOS patients or rodent models are characterized by hyperandrogenism, it may not be surprising that OCN levels may change in PCOS. Nevertheless, considering the relationship between OCN and glucose metabolism and energy metabolism, especially its role in increasing insulin secretion and enhancing insulin sensitivity (Ferron et al. 2012, Sabek et al. 2015), it is possible to speculate that uOCN may play a role in PCOS. OCN loss-of-function or gain-of-function studies on cell or animal models may help to identify this question. (III) What is the expression pattern of Gprc6a on the ovaries of female patients or rodent models with PCOS compared to the controls? It is known that the stimulation of testosterone production by uOCN is mediated by Gprc6a (De Toni et al. 2019), whose expression in WT ovary is quite low at mRNA level and is undetectable at protein level (Wellendorph & Brauner-Osborne 2004). Further work is needed to clarify the levels of expression of uOCN and Gprc6a in the ovaries, in the absence and presence of PCOS.

Could OCN be a possible marker for pubertal development disorders?

Puberty entails dramatic hormonal changes that cause increased growth spurts and bone acquisition, making it an important time for developmental processes (Lee et al. 2018). The onset of puberty is closely related to HPG axis and an increase in calcium utilization is associated with the early physical signs of puberty (Saggese et al. 2002). As we discussed above, OCN is not only a marker for osteoblast activity and bone formation that can facilitate mineral deposition and bone remodeling in the presence of calcium, but also can stimulate testosterone production from the testis and may act directly on the hypothalamus and pituitary, at least in animal models. In this context, it would be interesting to know whether there could be a possible link between OCN and pubertal development, or whether it could simply serve as a marker for the pubertal development disorders. Indeed, although there are few studies at present, a possible association between OCN and pubertal development disorders has been reported. Central precocious puberty (CPP) is defined as the activation of the HPG axis before the age of 8 in girls and 9 in boys, diagnosed by peak LH levels of ≥ 5.0 IU/L after stimulation with GnRH (Wheeler & Styne 1991). In a retrospective study, Kee-Hyoung Lee et al. included 100 CPP girls and 106 non-CPP girls, both of whom showed breast budding before the age of 8 and whose bone age was more advanced than their chronological age. They found that serum OCN levels were significantly higher in the CPP group and it was associated with an increase in bone age and LH peak, suggesting a possible the correlation between serum OCN and the onset of puberty in girls (Lee et al. 2018). However, another study investigating 244 patients with precocious puberty or constitutional delay of puberty reported although OCN was found to be highest among adolescents with precocious puberty and advanced pubertal development and lowest among patients with constitutional delay of puberty, no difference in OCN concentrations was observed between boys with advanced skeletal age and those with delayed skeletal age (Schundeln et al. 2017). The differences in the results from these two studies in terms of bone development majorly may be due to different sex, and also different nationality, or age. However, the number of studies showing such relations between OCN and puberty are scarce and more studies would be needed to define OCN as a standard marker for pubertal development or its related disorders.

Conclusions

Bone is an emerging endocrine organ that possesses roles in metabolic regulation and male reproduction. Of interest, it may play a role in the CNS. We have discussed the evidence that OCN, an osteoblast secreted hormone, influences components of the HPG axis to regulate male fertility, and the possible interaction of a bone-pancreas axis. While a role for OCN in female fertility and PCOS can be postulated, further research is needed to confirm or deny this.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81671518).

Author contribution statement

C S, J Y and W L contributed to the conception of the review, collected the related information, drafted and modified the manuscript.

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  • Guo XZ, Shan C, Hou YF, Zhu G, Tao B, Sun LH, Zhao HY, Ning G, Li ST & Liu JM 2018 Osteocalcin ameliorates motor dysfunction in a 6-hydroxydopamine-induced Parkinson’s disease rat model Through AKT/GSK3beta signaling. Frontiers in Molecular Neuroscience 11 343. (https://doi.org/10.3389/fnmol.2018.00343)

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  • Herbison AE & Moenter SM 2011 Depolarising and hyperpolarising actions of GABA(A) receptor activation on gonadotrophin-releasing hormone neurones: towards an emerging consensus. Journal of Neuroendocrinology 23 557569. (https://doi.org/10.1111/j.1365-2826.2011.02145.x)

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  • Holt R, Juel Mortensen L, Harpelunde Poulsen K, Nielsen JE, Frederiksen H, Jørgensen N, Jørgensen A, Juul A & Blomberg Jensen M 2020 Vitamin D and sex steroid production in men with normal or impaired Leydig cell function. Journal of Steroid Biochemistry and Molecular Biology 199 105589. (https://doi.org/10.1016/j.jsbmb.2020.105589)

    • Search Google Scholar
    • Export Citation
  • Kalra SP, Dube MG & Iwaniec UT 2009 Leptin increases osteoblast-specific osteocalcin release through a hypothalamic relay. Peptides 30 967973. (https://doi.org/10.1016/j.peptides.2009.01.020)

    • Search Google Scholar
    • Export Citation
  • Kanazawa I, Tanaka K, Ogawa N, Yamauchi M, Yamaguchi T & Sugimoto T 2013 Undercarboxylated osteocalcin is positively associated with free testosterone in male patients with type 2 diabetes mellitus. Osteoporosis International 24 11151119. (https://doi.org/10.1007/s00198-012-2017-7)

    • Search Google Scholar
    • Export Citation
  • Karsenty G 2014 Broadening the role of osteocalcin in Leydig cells. Endocrinology 155 41154116. (https://doi.org/10.1210/en.2014-1703)

  • Khrimian L, Obri A & Karsenty G 2017a Modulation of cognition and anxiety-like behavior by bone remodeling. Molecular Metabolism 6 16101615. (https://doi.org/10.1016/j.molmet.2017.10.001)

    • Search Google Scholar
    • Export Citation
  • Khrimian L, Obri A, Ramos-Brossier M, Rousseaud A, Moriceau S, Nicot AS, Mera P, Kosmidis S, Karnavas T & Saudou F et al. 2017b Gpr158 mediates osteocalcin's regulation of cognition. Journal of Experimental Medicine 214 28592873.

    • Search Google Scholar
    • Export Citation
  • Kirmani S, Atkinson EJ, Melton LJ 3rd, Riggs BL, Amin S & Khosla S 2011 Relationship of testosterone and osteocalcin levels during growth. Journal of Bone and Mineral Research 26 22122216. (https://doi.org/10.1002/jbmr.421)

    • Search Google Scholar
    • Export Citation
  • Kosmidis S, Polyzos A, Harvey L, Youssef M, Denny CA, Dranovsky A & Kandel ER 2018 RbAp48 protein is a critical component of GPR158/OCN signaling and ameliorates age-related memory loss. Cell Reports 25 959.e6–973.e6. (https://doi.org/10.1016/j.celrep.2018.09.077)

    • Search Google Scholar
    • Export Citation
  • Kuang D, Yao Y, Lam J, Tsushima RG & Hampson DR 2005 Cloning and characterization of a family C orphan G-protein coupled receptor. Journal of Neurochemistry 93 383391. (https://doi.org/10.1111/j.1471-4159.2005.03025.x)

    • Search Google Scholar
    • Export Citation
  • Lee AJ, Hodges S & Eastell R 2000 Measurement of osteocalcin. Annals of Clinical Biochemistry 37 432446. (https://doi.org/10.1177/000456320003700402)

    • Search Google Scholar
    • Export Citation
  • Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R, Mee PJ, Mckee MD & Jung DY et al. 2007 Endocrine regulation of energy metabolism by the skeleton. Cell 130 456469. (https://doi.org/10.1016/j.cell.2007.05.047)

    • Search Google Scholar
    • Export Citation
  • Lee WY, Jung G, Kim HR, Nam HK, Rhie YJ & Lee KH 2018 Serum osteocalcin levels in girls with central precocious puberty: relation to the onset of puberty. Tohoku Journal of Experimental Medicine 245 239243. (https://doi.org/10.1620/tjem.245.239)

    • Search Google Scholar
    • Export Citation
  • Li Y & Li K 2014 Osteocalcin induces growth hormone/insulin-like growth factor-1 system by promoting testosterone synthesis in male mice. Hormone and Metabolic Research 46 768773. (https://doi.org/10.1055/s-0034-1371869)

    • Search Google Scholar
    • Export Citation
  • Li J, Zhang H, Yang C, Li Y & Dai Z 2016 An overview of osteocalcin progress. Journal of Bone and Mineral Metabolism 34 367379. (https://doi.org/10.1007/s00774-015-0734-7)

    • Search Google Scholar
    • Export Citation
  • Liao M, Guo X, Yu X, Pang G, Zhang S, Li J, Tan A, Gao Y, Yang X & Zhang H et al. 2013 Role of metabolic factors in the association between osteocalcin and testosterone in Chinese men. Journal of Clinical Endocrinology and Metabolism 98 34633469. (https://doi.org/10.1210/jc.2013-1805)

    • Search Google Scholar
    • Export Citation
  • Limonard EJ, Van Schoor NM, De Jongh RT, Lips P, Fliers E & Bisschop PH 2015 Osteocalcin and the pituitary-gonadal axis in older men: a population-based study. Clinical Endocrinology 82 753759. (https://doi.org/10.1111/cen.12660)

    • Search Google Scholar
    • Export Citation
  • Lingaiah S, Morin-Papunen L, Piltonen T, Puurunen J, Sundstrom-Poromaa I, Stener-Victorin E, Bloigu R, Risteli J & Tapanainen JS 2017 Bone markers in polycystic ovary syndrome: a multicentre study. Clinical Endocrinology 87 673679. (https://doi.org/10.1111/cen.13456)

    • Search Google Scholar
    • Export Citation
  • Liu DM, Mosialou I & Liu JM 2018 Bone: another potential target to treat, prevent and predict diabetes. Diabetes, Obesity and Metabolism 20 18171828. (https://doi.org/10.1111/dom.13330)

    • Search Google Scholar
    • Export Citation
  • Mera P, Laue K, Ferron M, Confavreux C, Wei J, Galan-Diez M, Lacampagne A, Mitchell SJ, Mattison JA & Chen Y et al. 2016 Osteocalcin signaling in myofibers is necessary and sufficient for optimum adaptation to exercise. Cell Metabolism 23 10781092. (https://doi.org/10.1016/j.cmet.2016.05.004)

    • Search Google Scholar
    • Export Citation
  • Moore AM, Prescott M, Marshall CJ, Yip SH & Campbell RE 2015 Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome. PNAS 112 596601. (https://doi.org/10.1073/pnas.1415038112)

    • Search Google Scholar
    • Export Citation
  • Oury F, Sumara G, Sumara O, Ferron M, Chang H, Smith CE, Hermo L, Suarez S, Roth BL & Ducy P et al. 2011 Endocrine regulation of male fertility by the skeleton. Cell 144 796809. (https://doi.org/10.1016/j.cell.2011.02.004)

    • Search Google Scholar
    • Export Citation
  • Oury F, Ferron M, Huizhen W, Confavreux C, Xu L, Lacombe J, Srinivas P, Chamouni A, Lugani F & Lejeune H et al. 2013a Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis. Journal of Clinical Investigation 123 24212433. (https://doi.org/10.1172/JCI65952)

    • Search Google Scholar
    • Export Citation
  • Oury F, Khrimian L, Denny CA, Gardin A, Chamouni A, Goeden N, Huang YY, Lee H, Srinivas P & Gao XB et al. 2013b Maternal and offspring pools of osteocalcin influence brain development and functions. Cell 155 228241. (https://doi.org/10.1016/j.cell.2013.08.042)

    • Search Google Scholar
    • Export Citation
  • Oury F, Ferron M, Huizhen W, Confavreux C, Xu L, Lacombe J, Srinivas P, Chamouni A, Lugani F & Lejeune H et al. 2015 Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis. Journal of Clinical Investigation 125 2180. (https://doi.org/10.1172/JCI81812)

    • Search Google Scholar
    • Export Citation
  • Pi M, Faber P, Ekema G, Jackson PD, Ting A, Wang N, Fontilla-Poole M, Mays RW, Brunden KR & Harrington JJ et al. 2005 Identification of a novel extracellular cation-sensing G-protein-coupled receptor. Journal of Biological Chemistry 280 4020140209. (https://doi.org/10.1074/jbc.M505186200)

    • Search Google Scholar
    • Export Citation
  • Pi M, Chen L, Huang MZ, Zhu W, Ringhofer B, Luo J, Christenson L, Li B, Zhang J & Jackson PD et al. 2008 GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome. PLoS ONE 3 e3858. (https://doi.org/10.1371/journal.pone.0003858)

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  • Pi M, Parrill AL & Quarles LD 2010 GPRC6A mediates the non-genomic effects of steroids. Journal of Biological Chemistry 285 3995339964. (https://doi.org/10.1074/jbc.M110.158063)

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    • Export Citation
  • Pi M & Quarles LD 2012 Multiligand specificity and wide tissue expression of GPRC6A reveals new endocrine networks. Endocrinology 153 20622069. (https://doi.org/10.1210/en.2011-2117)

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  • Piaggi P, Masindova I, Muller YL, Mercader J, Wiessner GB, Chen PSIGMA Type 2 Diabetes Consortium, Kobes S, Hsueh WC & Mongalo M et al. 2017 A genome-wide association study using a custom genotyping array identifies variants in GPR158 associated with reduced energy expenditure in American Indians. Diabetes 66 22842295. (https://doi.org/10.2337/db16-1565)

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  • Rosenfield RL & Ehrmann DA 2016 The pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocrine Reviews 37 467520. (https://doi.org/10.1210/er.2015-1104)

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  • Sabek OM, Nishimoto SK, Fraga D, Tejpal N, Ricordi C & Gaber AO 2015 Osteocalcin effect on human beta-cells mass and function. Endocrinology 156 31373146. (https://doi.org/10.1210/EN.2015-1143)

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  • Saggese G, Baroncelli GI & Bertelloni S 2002 Puberty and bone development. Best Practice and Research: Clinical Endocrinology and Metabolism 16 5364. (https://doi.org/10.1053/beem.2001.0180)

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  • Schundeln MM, Bader L, Kiewert C, Herrmann R, Fuhrer D, Hauffa BP & Grasemann C 2017 Plasma concentrations of osteocalcin are associated with the timing of pubertal progress in boys. Journal of Pediatric Endocrinology and Metabolism 30 141147. (https://doi.org/10.1515/jpem-2016-0243)

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  • Shan C, Ghosh A, Guo XZ, Wang SM, Hou YF, Li ST & Liu JM 2019 Roles for osteocalcin in brain signalling: implications in cognition- and motor-related disorders. Molecular Brain 12 23. (https://doi.org/10.1186/s13041-019-0444-5)

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  • Wei J, Hanna T, Suda N, Karsenty G & Ducy P 2014 Osteocalcin promotes beta-cell proliferation during development and adulthood through Gprc6a. Diabetes 63 10211031. (https://doi.org/10.2337/db13-0887)

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  • Wheeler MD & Styne DM 1991 Drug treatment in precocious puberty. Drugs 41 717728. (https://doi.org/10.2165/00003495-199141050-00004)

  • Yeap BB, Alfonso H, Chubb SA, Gauci R, Byrnes E, Beilby JP, Ebeling PR, Handelsman DJ, Allan CA & Grossmann M et al. 2015 Higher serum undercarboxylated osteocalcin and other bone turnover markers are associated with reduced diabetes risk and lower estradiol concentrations in older men. Journal of Clinical Endocrinology and Metabolism 100 6371. (https://doi.org/10.1210/jc.2014-3019)

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Society for Endocrinology

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    Possible regulations of OCN on hypothalamic–pituitary–testis axis. OCN can pass through the blood-brain barrier and then bind to the hypothalamus and pituitary. By possible regulations on GnRH neurons and GABAergic neurons (Herbison & Moenter 2011), OCN may modulate the GnRH/LH pulse frequency, thus playing a role in regulating the LH amplitude and then the functions of testis. Previous studies have shown that following its binding to Gprc6a in Leydig cells, OCN can favor cAMP production that leads to the activation of the transcription factor CREB (cAMP response element binding). CREB activates the expression of several genes encoding the enzymes that are necessary for testosterone biosynthesis, such as StAR, Cyp11a, 3b-HSD and Cyp17 (Oury et al. 2011).

  • Berger JM, Singh P, Khrimian L, Morgan DA, Chowdhury S, Arteaga-Solis E, Horvath TL, Domingos AI, Marsland AL & Yadav VK et al. 2019 Mediation of the acute stress response by the skeleton. Cell Metabolism 30 890.e8–902.e8. (https://doi.org/10.1016/j.cmet.2019.08.012)

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  • Bisby MA 1980 Axonal transport of labeled protein and regeneration rate in nerves of streptozocin-diabetic rats. Experimental Neurology 69 7484. (https://doi.org/10.1016/0014-4886(80)90144-2)

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  • De Toni L, De Filippis V, Tescari S, Ferigo M, Ferlin A, Scattolini V, Avogaro A, Vettor R & Foresta C 2014 Uncarboxylated osteocalcin stimulates 25-hydroxy vitamin D production in Leydig cell line through a GPRC6a-dependent pathway. Endocrinology 155 42664274. (https://doi.org/10.1210/en.2014-1283)

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  • De Toni L, Guidolin D, De Filippis V, Tescari S, Strapazzon G, Santa Rocca M, Ferlin A, Plebani M & Foresta C 2016 Osteocalcin and sex hormone binding globulin compete on a specific binding site of GPRC6A. Endocrinology 157 44734486. (https://doi.org/10.1210/en.2016-1312)

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  • De Toni L, Guidolin D, De Filippis V, Peterle D, Rocca MS, Di Nisio A, De Rocco Ponce M & Foresta C 2019 SHBG141-161 domain-peptide stimulates GPRC6A-mediated response in leydig and β-langerhans cell lines. Scientific Reports 9 1943219432. (https://doi.org/10.1038/s41598-019-55941-x)

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  • Diegel CR, Hann S, Ayturk UM, Hu JCW, Lim KE, Droscha CJ, Madaj ZB, Foxa GE, Izaguirre I & Transgenics Core VVA et al. 2020 An osteocalcin-deficient mouse strain without endocrine abnormalities. PLoS Genetics 16 e1008361. (https://doi.org/10.1371/journal.pgen.1008361)

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  • Dirckx N, Moorer MC, Clemens TL & Riddle RC 2019 The role of osteoblasts in energy homeostasis. Nature Reviews: Endocrinology 15 651665. (https://doi.org/10.1038/s41574-019-0246-y)

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  • Ehrmann DA 2005 Polycystic ovary syndrome. New England Journal of Medicine 352 12231236. (https://doi.org/10.1056/NEJMra041536)

  • Elefteriou F, Campbell P & Ma Y 2014 Control of bone remodeling by the peripheral sympathetic nervous system. Calcified Tissue International 94 140151. (https://doi.org/10.1007/s00223-013-9752-4)

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  • Ferron M, Wei J, Yoshizawa T, Del Fattore A, Depinho RA, Teti A, Ducy P & Karsenty G 2010 Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell 142 296308. (https://doi.org/10.1016/j.cell.2010.06.003)

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  • Ferron M, Mckee MD, Levine RL, Ducy P & Karsenty G 2012 Intermittent injections of osteocalcin improve glucose metabolism and prevent type 2 diabetes in mice. Bone 50 568575. (https://doi.org/10.1016/j.bone.2011.04.017)

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  • Fulzele K, Riddle RC, Digirolamo DJ, Cao X, Wan C, Chen D, Faugere MC, Aja S, Hussain MA & Brüning JC et al. 2010 Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell 142 309319. (https://doi.org/10.1016/j.cell.2010.06.002)

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  • Glatigny M, Moriceau S, Rivagorda M, Ramos-Brossier M, Nascimbeni AC, Lante F, Shanley MR, Boudarene N, Rousseaud A & Friedman AK et al. 2019 Autophagy is required for memory formation and reverses age-related memory decline. Current Biology 29 435.e8–448.e8. (https://doi.org/10.1016/j.cub.2018.12.021)

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  • Guo XZ, Shan C, Hou YF, Zhu G, Tao B, Sun LH, Zhao HY, Ning G, Li ST & Liu JM 2018 Osteocalcin ameliorates motor dysfunction in a 6-hydroxydopamine-induced Parkinson’s disease rat model Through AKT/GSK3beta signaling. Frontiers in Molecular Neuroscience 11 343. (https://doi.org/10.3389/fnmol.2018.00343)

    • Search Google Scholar
    • Export Citation
  • Herbison AE & Moenter SM 2011 Depolarising and hyperpolarising actions of GABA(A) receptor activation on gonadotrophin-releasing hormone neurones: towards an emerging consensus. Journal of Neuroendocrinology 23 557569. (https://doi.org/10.1111/j.1365-2826.2011.02145.x)

    • Search Google Scholar
    • Export Citation
  • Holt R, Juel Mortensen L, Harpelunde Poulsen K, Nielsen JE, Frederiksen H, Jørgensen N, Jørgensen A, Juul A & Blomberg Jensen M 2020 Vitamin D and sex steroid production in men with normal or impaired Leydig cell function. Journal of Steroid Biochemistry and Molecular Biology 199 105589. (https://doi.org/10.1016/j.jsbmb.2020.105589)

    • Search Google Scholar
    • Export Citation
  • Kalra SP, Dube MG & Iwaniec UT 2009 Leptin increases osteoblast-specific osteocalcin release through a hypothalamic relay. Peptides 30 967973. (https://doi.org/10.1016/j.peptides.2009.01.020)

    • Search Google Scholar
    • Export Citation
  • Kanazawa I, Tanaka K, Ogawa N, Yamauchi M, Yamaguchi T & Sugimoto T 2013 Undercarboxylated osteocalcin is positively associated with free testosterone in male patients with type 2 diabetes mellitus. Osteoporosis International 24 11151119. (https://doi.org/10.1007/s00198-012-2017-7)

    • Search Google Scholar
    • Export Citation
  • Karsenty G 2014 Broadening the role of osteocalcin in Leydig cells. Endocrinology 155 41154116. (https://doi.org/10.1210/en.2014-1703)

  • Khrimian L, Obri A & Karsenty G 2017a Modulation of cognition and anxiety-like behavior by bone remodeling. Molecular Metabolism 6 16101615. (https://doi.org/10.1016/j.molmet.2017.10.001)

    • Search Google Scholar
    • Export Citation
  • Khrimian L, Obri A, Ramos-Brossier M, Rousseaud A, Moriceau S, Nicot AS, Mera P, Kosmidis S, Karnavas T & Saudou F et al. 2017b Gpr158 mediates osteocalcin's regulation of cognition. Journal of Experimental Medicine 214 28592873.

    • Search Google Scholar
    • Export Citation
  • Kirmani S, Atkinson EJ, Melton LJ 3rd, Riggs BL, Amin S & Khosla S 2011 Relationship of testosterone and osteocalcin levels during growth. Journal of Bone and Mineral Research 26 22122216. (https://doi.org/10.1002/jbmr.421)

    • Search Google Scholar
    • Export Citation
  • Kosmidis S, Polyzos A, Harvey L, Youssef M, Denny CA, Dranovsky A & Kandel ER 2018 RbAp48 protein is a critical component of GPR158/OCN signaling and ameliorates age-related memory loss. Cell Reports 25 959.e6–973.e6. (https://doi.org/10.1016/j.celrep.2018.09.077)

    • Search Google Scholar
    • Export Citation
  • Kuang D, Yao Y, Lam J, Tsushima RG & Hampson DR 2005 Cloning and characterization of a family C orphan G-protein coupled receptor. Journal of Neurochemistry 93 383391. (https://doi.org/10.1111/j.1471-4159.2005.03025.x)

    • Search Google Scholar
    • Export Citation
  • Lee AJ, Hodges S & Eastell R 2000 Measurement of osteocalcin. Annals of Clinical Biochemistry 37 432446. (https://doi.org/10.1177/000456320003700402)

    • Search Google Scholar
    • Export Citation
  • Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R, Mee PJ, Mckee MD & Jung DY et al. 2007 Endocrine regulation of energy metabolism by the skeleton. Cell 130 456469. (https://doi.org/10.1016/j.cell.2007.05.047)

    • Search Google Scholar
    • Export Citation
  • Lee WY, Jung G, Kim HR, Nam HK, Rhie YJ & Lee KH 2018 Serum osteocalcin levels in girls with central precocious puberty: relation to the onset of puberty. Tohoku Journal of Experimental Medicine 245 239243. (https://doi.org/10.1620/tjem.245.239)

    • Search Google Scholar
    • Export Citation
  • Li Y & Li K 2014 Osteocalcin induces growth hormone/insulin-like growth factor-1 system by promoting testosterone synthesis in male mice. Hormone and Metabolic Research 46 768773. (https://doi.org/10.1055/s-0034-1371869)

    • Search Google Scholar
    • Export Citation
  • Li J, Zhang H, Yang C, Li Y & Dai Z 2016 An overview of osteocalcin progress. Journal of Bone and Mineral Metabolism 34 367379. (https://doi.org/10.1007/s00774-015-0734-7)

    • Search Google Scholar
    • Export Citation
  • Liao M, Guo X, Yu X, Pang G, Zhang S, Li J, Tan A, Gao Y, Yang X & Zhang H et al. 2013 Role of metabolic factors in the association between osteocalcin and testosterone in Chinese men. Journal of Clinical Endocrinology and Metabolism 98 34633469. (https://doi.org/10.1210/jc.2013-1805)

    • Search Google Scholar
    • Export Citation
  • Limonard EJ, Van Schoor NM, De Jongh RT, Lips P, Fliers E & Bisschop PH 2015 Osteocalcin and the pituitary-gonadal axis in older men: a population-based study. Clinical Endocrinology 82 753759. (https://doi.org/10.1111/cen.12660)

    • Search Google Scholar
    • Export Citation
  • Lingaiah S, Morin-Papunen L, Piltonen T, Puurunen J, Sundstrom-Poromaa I, Stener-Victorin E, Bloigu R, Risteli J & Tapanainen JS 2017 Bone markers in polycystic ovary syndrome: a multicentre study. Clinical Endocrinology 87 673679. (https://doi.org/10.1111/cen.13456)

    • Search Google Scholar
    • Export Citation
  • Liu DM, Mosialou I & Liu JM 2018 Bone: another potential target to treat, prevent and predict diabetes. Diabetes, Obesity and Metabolism 20 18171828. (https://doi.org/10.1111/dom.13330)

    • Search Google Scholar
    • Export Citation
  • Mera P, Laue K, Ferron M, Confavreux C, Wei J, Galan-Diez M, Lacampagne A, Mitchell SJ, Mattison JA & Chen Y et al. 2016 Osteocalcin signaling in myofibers is necessary and sufficient for optimum adaptation to exercise. Cell Metabolism 23 10781092. (https://doi.org/10.1016/j.cmet.2016.05.004)

    • Search Google Scholar
    • Export Citation
  • Moore AM, Prescott M, Marshall CJ, Yip SH & Campbell RE 2015 Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome. PNAS 112 596601. (https://doi.org/10.1073/pnas.1415038112)

    • Search Google Scholar
    • Export Citation
  • Oury F, Sumara G, Sumara O, Ferron M, Chang H, Smith CE, Hermo L, Suarez S, Roth BL & Ducy P et al. 2011 Endocrine regulation of male fertility by the skeleton. Cell 144 796809. (https://doi.org/10.1016/j.cell.2011.02.004)

    • Search Google Scholar
    • Export Citation
  • Oury F, Ferron M, Huizhen W, Confavreux C, Xu L, Lacombe J, Srinivas P, Chamouni A, Lugani F & Lejeune H et al. 2013a Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis. Journal of Clinical Investigation 123 24212433. (https://doi.org/10.1172/JCI65952)

    • Search Google Scholar
    • Export Citation
  • Oury F, Khrimian L, Denny CA, Gardin A, Chamouni A, Goeden N, Huang YY, Lee H, Srinivas P & Gao XB et al. 2013b Maternal and offspring pools of osteocalcin influence brain development and functions. Cell 155 228241. (https://doi.org/10.1016/j.cell.2013.08.042)

    • Search Google Scholar
    • Export Citation
  • Oury F, Ferron M, Huizhen W, Confavreux C, Xu L, Lacombe J, Srinivas P, Chamouni A, Lugani F & Lejeune H et al. 2015 Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis. Journal of Clinical Investigation 125 2180. (https://doi.org/10.1172/JCI81812)

    • Search Google Scholar
    • Export Citation
  • Pi M, Faber P, Ekema G, Jackson PD, Ting A, Wang N, Fontilla-Poole M, Mays RW, Brunden KR & Harrington JJ et al. 2005 Identification of a novel extracellular cation-sensing G-protein-coupled receptor. Journal of Biological Chemistry 280 4020140209. (https://doi.org/10.1074/jbc.M505186200)

    • Search Google Scholar
    • Export Citation
  • Pi M, Chen L, Huang MZ, Zhu W, Ringhofer B, Luo J, Christenson L, Li B, Zhang J & Jackson PD et al. 2008 GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome. PLoS ONE 3 e3858. (https://doi.org/10.1371/journal.pone.0003858)

    • Search Google Scholar
    • Export Citation
  • Pi M, Parrill AL & Quarles LD 2010 GPRC6A mediates the non-genomic effects of steroids. Journal of Biological Chemistry 285 3995339964. (https://doi.org/10.1074/jbc.M110.158063)

    • Search Google Scholar
    • Export Citation
  • Pi M & Quarles LD 2012 Multiligand specificity and wide tissue expression of GPRC6A reveals new endocrine networks. Endocrinology 153 20622069. (https://doi.org/10.1210/en.2011-2117)

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