The Role of Myosin X in BMPs Promotion of SMAD 1/5 in Osteoclast Formation and Function

Abstract

Novel therapeutic strategies that target osteoclasts are needed for many orthopedic, craniofacial and cancer applications. Incomplete understanding of the factors that regulate osteoclasts limits this development. Currently, bone morphogenetic proteins (BMPs) are used to promote healing of open fractures, bone grafts and non-union fractures. Bone healing requires synthesis of new bone by osteoblasts and the removal of old or damaged bone matrix by osteoclasts. Although BMPs have been widely studied as stimulators of osteoblastic bone formation, it has also been shown that BMPs directly increase osteoclast formation, however the mechanism behind this enhancement is not completely understood. Two potential candidates responsible for BMPs enhancement of osteoclast formation could be SMADs, components of the canonical BMP signaling pathway, and MYO10, a regulator of the osteoclast cytoskeleton. The data presented in this thesis demonstrates that loss of SMAD1/5 expression by osteoclasts in in vitro cultures of osteoclasts inhibits osteoclast differentiation and activity. However, the loss of SMAD1/5 expression in osteoclasts and macrophages in a mouse model leads to enhance osteoclast differentiation and activity. Interestingly bone formation is also increased in the mouse model with decreased SMAD1/5 expression suggesting that SMAD1/5 signaling in osteoclasts may regulate coupling between osteoclast and osteoblast activity. Lastly MYO10 besides playing a role in osteoclast activity also plays a role in regulating osteoclast differentiation. Data presented demonstrates that loss of MYO10 expression correlates with changes in the osteoclast cytoskeleton which impacts the ability of osteoclasts to fuse. By gaining knowledge of regulators of osteoclastogenesis and the mechanism by which they modulate osteoclast differentiation and activity, we will better understand the etiology of osteoclast diseases and provide novel insight into future therapies.