title: Loss of BMPR2 leads to high bone mass due to increased osteoblast activity.
abstract: Imbalances in the ratio of bone morphogenetic protein (BMP) versus activin and TGFβ signaling are increasingly associated with human diseases yet the mechanisms mediating this relationship remain unclear. The type 2 receptors ACVR2A and ACVR2B bind BMPs and activins but the type 2 receptor BMPR2 only binds BMPs, suggesting that type 2 receptor utilization might play a role in mediating the interaction of these pathways. We tested this hypothesis in the mouse skeleton, where bone mass is reciprocally regulated by BMP signaling and activin and TGFβ signaling. We found that deleting Bmpr2 in mouse skeletal progenitor cells (Bmpr2-cKO mice) selectively impaired activin signaling but had no effect on BMP signaling, resulting in an increased bone formation rate and high bone mass. Additionally, activin sequestration had no effect on bone mass in Bmpr2-cKO mice but increased bone mass in wild-type mice. Our findings suggest a novel model whereby BMPR2 availability alleviates receptor-level competition between BMPs and activins and where utilization of ACVR2A and ACVR2B by BMPs comes at the expense of activins. As BMP and activin pathway modulation are of current therapeutic interest, our findings provide important mechanistic insight into the relationship between these pathways in human health.
authors: Department of Biomedical Science, Marian University College of Osteopathic Medicine, Indianapolis, IN 46222, USA Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors: Jonathan W
authors: JW
authors: Lowery
authors: Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors: Giuseppe
authors: G
authors: Intini
authors: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors: Laura
authors: L
authors: Gamer
authors: Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA Department of Physiology, Faculty of Dentistry, Chulalongkorn University, Bangkok, 10330, Thailand.
authors: Sutada
authors: S
authors: Lotinun
authors: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors: Valerie S
authors: VS
authors: Salazar
authors: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors: Satoshi
authors: S
authors: Ote
authors: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors: Karen
authors: K
authors: Cox
authors: Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors: Roland
authors: R
authors: Baron
authors: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA Vicki_Rosen@hsdm.harvard.edu.
authors: Vicki
authors: V
authors: Rosen
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism; D028341:Activins / Q000378:metabolism; D000818:Animals; D001846:Bone Development; D001847:Bone Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019485:Bone Morphogenetic Proteins; D028341:Activins; D030301:Activin Receptors, Type II; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: Activin; BMP; BMPR2; Bone mass; Osteoblast; Osteoporosis