Grant: Operating Grant

Osteoclasts are the primary resorptive cells of bone and are crucial for normal bone turnover. They are large multinucleated cells that are formed through the fusion of mononucleated precursors that belong to the mononuclear phagocyte lineage. Once formed these cells actively resorb bone by developing specialized resorptive machinery. Cell migration, cell fusion and bone resoprtion all require the actin cytoskeleton which is regulated by the Rho family of small GTPases. Indeed the more potent, nitrogen-containing bisphosphonates used to reat osteoporosis inhibit osteoclast-mediated bone resorption by blocking post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. Filamin A is a ubiquitous actin binding protein which has been shown to be required for regulating the actin cytoskeleton and cell migration possibly through regulation of small GTPases. While it has been demonstrated recently that the Rho GTPases play significant roles in osteoclast function, their specific signaling roles in osteoclastogenesis and osteoclast function has not been fully defined. Moreover, there are currently no studies on the role of filamin A in osteoclastogenesis, a process that is highly dependent on actin dynamics. We have developed a transgenic mouse colony in which filamin A is selectively deleted in mouse monocytes/pre-osteoclasts. With this unique model we have preliminary data which indicates that filamin A regulates osteoclastogenesis, and does so via signaling through Rho GTPases. This grant will examine new elements of filamin A signaling that extend our understanding of the functions of this important actin binding protein in regulating bone physiology.