Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis

Abstract

The osteoblast-derived hormone osteocalcin promotes testosterone biosynthesis in the mouse testis by binding to GPRC6A in Leydig cells. Interestingly, Osteocalcin-deficient mice exhibit increased levels of luteinizing hormone (LH), a pituitary hormone that regulates sex steroid synthesis in the testes. These observations raise the question of whether LH regulates osteocalcin's reproductive effects. Additionally, there is growing evidence that osteocalcin levels are a reliable marker of insulin secretion and sensitivity and circulating levels of testosterone in humans, but the endocrine function of osteocalcin is unclear. Using mouse models, we found that osteocalcin and LH act in 2 parallel pathways and that osteocalcin-stimulated testosterone synthesis is positively regulated by bone resorption and insulin signaling in osteoblasts. To determine the importance of osteocalcin in humans, we analyzed a cohort of patients with primary testicular failure and identified 2 individuals harboring the same heterozygous missense variant in one of the transmembrane domains of GPRC6A, which prevented the receptor from localizing to the cell membrane. This study uncovers the existence of a second endocrine axis that is necessary for optimal male fertility in the mouse and suggests that osteocalcin modulates reproductive function in humans.

Testicular Function and Bone in Young Men with Severe Childhood-Onset Obesity

“…Interleukin 6 has been shown to inhibit the differentiation of rat stem Leydig cells leading to downregulation of steroidogenic enzymes and lower serum testosterone levels [34]. Previous studies have suggested that osteoblast-derived OC may stimulate testosterone production [16]. Serum OC concentrations were lower in males with childhood-onset obesity than in controls, but did not correlate with serum testosterone concentrations in the males with childhood-onset obesity.…”

“…Recent evidence suggests the presence of endocrine regulation between bone and testes beyond sex steroids – the bone-testis axis. Osteoblast-derived uncarboxylated osteocalcin (OC) stimulates testosterone production in the testes in mice [16]. In humans, serum total OC levels correlate positively with testosterone levels in adult men [17, 18] and pubertal boys [19].…”

Endocrine role of bone: recent and emerging perspectives beyond osteocalcin

“…Similarly, it appears that the reproductive function of OC translates to humans, with the identification of a positive association between OC and testosterone serum levels in the general population, patients with bone disorders and patients with T2DM (Hannemann et al 2013, Kanazawa et al 2013. Furthermore, two subjects were identified from a cohort of patients displaying testicular failure who harboured a heterozygous missense variant in one of the transmembrane domains of GPRC6A, giving credence to a role of OC function in humans (Oury et al 2013;reviewed in Karsenty & Oury (2014)). …”

“…GPRC6A has been shown to be integral in the promotion of b-cell proliferation during development and adulthood via OC, thus highlighting GPRC6A as an important receptor for skeletal-tissue-mediated energy regulation via the pancreas (Pi et al 2011, Wei et al 2014a. Most recently, Oury et al (2013) demonstrated that OC acts via a pancreas-bone-testis axis, such that OC-stimulated testosterone synthesis is positively regulated by insulin signalling in osteoblasts and is independent of luteinising hormone (LH). No connection between Ptprv K/K and Oc K/K mice in osteoblast-stimulated oestradiol production was identified, illustrating that the regulatory mechanisms of fertility of male and female mice are vastly distinct (Oury et al 2011).…”

Has sclerostin a true endocrine metabolic action complementary to osteocalcin in older men?

“…Osteocalcin is a bone-secreted hormone regulating the secretion of insulin, adiponectin and testosterone in rodents and humans [1][2][3][4]. Furthermore, lower serum osteocalcin was associated with greater insulin resistance in type 2 diabetes patients [5,6], metabolic syndrome (MetS) [7,8] and vascular calcifications [9].…”