Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis.Librarian's Comment : Osteocalcin is a multifunctional hormone secreted by osteoblasts. Amongst other it acts on pancreatic ß cells to increase insulin secretion and on Leydig cells to favor testosterone biosynthesis following its binding to a specific receptor, GPRC6A. Male mice lacking Osteocalcin or this receptor specifically in Leydig cells demonstrate a marked reduction of circulating testosterone levels and reduced fertility. In Osteocalcin-null (Osteocalcin–/–) mice LH levels are increased. Using mouse models, the authors claim that osteocalcin and LH act in 2 parallel pathways and that testosterone synthesis stimulated by osteocalcin is positively regulated by bone resorption and insulin signaling in osteoblasts. This paper provides evidence through cell-specific gene deletion experiments in the mouse that support the existence of a pancreas-bone-testis axis favoring male fertility. This new pathway acts in parallel to and independently of the established hypothalamus-pituitary-testis axis. Moreover, in 2 patients with testicular failure a mutation in the GPRC6A osteocalcin receptor results in a dominant negative mutation.
Published in : The Journal of clinical investigation
Authors : Oury F, Ferron M, Huizhen W, Confavreux C, Xu L, Lacombe J, Srinivas P, Chamouni A, Lugani F, Lejeune H, Kumar TR, Plotton I, Karsenty G
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.