title: Osteocalcin promotes β-cell proliferation during development and adulthood through Gprc6a.
abstract: Expanding β-cell mass through β-cell proliferation is considered a potential therapeutic approach to treat β-cell failure in diabetic patients. A necessary step toward achieving this goal is to identify signaling pathways that regulate β-cell proliferation in vivo. Here we show that osteocalcin, a bone-derived hormone, regulates β-cell replication in a cyclin D1-dependent manner by signaling through the Gprc6a receptor expressed in these cells. Accordingly, mice lacking Gprc6a in the β-cell lineage only are glucose intolerant due to an impaired ability to produce insulin. Remarkably, this regulation occurs during both the perinatal peak of β-cell proliferation and in adulthood. Hence, the loss of osteocalcin/Gprc6a signaling has a profound effect on β-cell mass accrual during late pancreas morphogenesis. This study extends the endocrine role of osteocalcin to the developmental period and establishes osteocalcin/Gprc6a signaling as a major regulator of β-cell endowment that can become a potential target for β-cell proliferative therapies.
authors.affiliation: Department of Genetics & Development, College of Physicians and Surgeons, Columbia University, New York, NY.
authors.forename: Jianwen
authors.initials: J
authors.lastname: Wei
authors.forename: Timothy
authors.initials: T
authors.lastname: Hanna
authors.forename: Nina
authors.initials: N
authors.lastname: Suda
authors.forename: Gerard
authors.initials: G
authors.lastname: Karsenty
authors.forename: Patricia
authors.initials: P
authors.lastname: Ducy
mesh_terms: D000375:Aging; D000818:Animals; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000032:analysis; D018149:Glucose Intolerance / Q000209:etiology; D007328:Insulin / Q000096:biosynthesis; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015675:Osteocalcin / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015398:Signal Transduction
chemical_list: C515750:GPRC6A protein, mouse; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D015675:Osteocalcin; D019938:Cyclin D1