Adult Bone Mass Regulation by Type 2 BMP Receptors

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DESCRIPTION (provided by applicant): Osteoporosis, a disease of low bone mineral density associated with increased risk of fracture, is both a significant health problem and a considerable socioeconomic burden and there remains an unmet need for new therapies that would reduce the incidence of osteoporosis in the US. Bone Morphogenetic Protein (BMP) signaling plays a prominent role in skeletal development and fracture repair, and there is increasing evidence positively linking BMP signaling to bone formation in the adult skeleton. Here, we focus on the cellular and molecular events that regulate BMP signaling in bone cells. We show, using a mouse model developed in our lab that changing the composition of the type 2 BMP receptor pool present on bone forming cells influences the amount of bone they produce in vivo. Surprisingly, when mice lack the type 2 BMP receptor, BMPR2, on bone forming cells, normal levels of BMP signaling in bone still occur, but there is an unexpected reduction in the level of Activin/TGFb signaling. In these mice, the cells that build bone work harder while the cells that destroy bone work at a normal pace, causing the animals to have high bone mass. We believe that our results are due to the fact that the remaining type 2 receptors present on bone forming cells, ACVR2A/B, are shared between BMPs and Activins, another group of signaling molecules that are known to negatively affect bone formation. BMPs and Activins now have to compete for the remaining type 2 receptors, and information suggests that this competition would favor BMPs. Collectively, this leads us to hypothesize that interplay between BMP and Activin/TGFb signaling regulates bone formation in the adult skeleton. In this proposal, we explore two interrelated ideas that impact how we view the interaction of BMP and Activin/TGFb signaling in the adult skeleton. First, we suggest that competition between BMPs and Activins for shared type 2 receptors is a physiological event that influences bone formation in vivo. Second, we suggest that signaling antagonism between the BMP and Activin/TGFb pathways occurring downstream of receptor engagement is another means by which the bone mass is regulated in the adult skeleton. In three specific aims, we ask: Why does removing BMPR2 from bone cells affect Activin signaling? What is the cellular mechanism leading to high bone mass in mice lacking BMPR2 expression in bones? And, does Activin signaling antagonize BMP signaling in the skeleton? These studies will add to our understanding of how bone formation is regulated by interactions between the BMP and Activin/TGFb pathways and could identify future therapeutic approaches to treat bone diseases.