title: 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.
authors.affiliation: Department of Genetics and Development, Columbia University, New York, New York, USA.
authors.forename: Franck
authors.initials: F
authors.lastname: Oury
authors.forename: Mathieu
authors.initials: M
authors.lastname: Ferron
authors.forename: Wang
authors.initials: W
authors.lastname: Huizhen
authors.forename: Cyrille
authors.initials: C
authors.lastname: Confavreux
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.forename: Julie
authors.initials: J
authors.lastname: Lacombe
authors.forename: Prashanth
authors.initials: P
authors.lastname: Srinivas
authors.forename: Alexandre
authors.initials: A
authors.lastname: Chamouni
authors.forename: Francesca
authors.initials: F
authors.lastname: Lugani
authors.forename: Herve
authors.initials: H
authors.lastname: Lejeune
authors.forename: T Rajendra
authors.initials: TR
authors.lastname: Kumar
authors.forename: Ingrid
authors.initials: I
authors.lastname: Plotton
authors.forename: Gerard
authors.initials: G
authors.lastname: Karsenty
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D001862:Bone Resorption; D001842:Bone and Bones / Q000473:pathology*; D005799:Genes, Dominant; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006801:Humans; D007030:Hypothalamo-Hypophyseal System; D007328:Insulin / Q000502:physiology; D007986:Luteinizing Hormone / Q000502:physiology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009845:Oligospermia / Q000235:genetics* / Q000378:metabolism; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism; D015675:Osteocalcin / Q000502:physiology*; D010179:Pancreas / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013737:Testis / Q000473:pathology*; D013739:Testosterone / Q000096:biosynthesis
chemical_list: C488584:GPRC6A protein, human; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D015675:Osteocalcin; D013739:Testosterone; D007986:Luteinizing Hormone