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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 TGF? 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 TGF? 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.

SUBMITTER: Lowery JW 

PROVIDER: S-EPMC4379725 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Loss of BMPR2 leads to high bone mass due to increased osteoblast activity.

Lowery Jonathan W JW   Intini Giuseppe G   Gamer Laura L   Lotinun Sutada S   Salazar Valerie S VS   Ote Satoshi S   Cox Karen K   Baron Roland R   Rosen Vicki V  

Journal of cell science 20150206 7


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 reciproc  ...[more]

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