Various members of the Ras superfamily of small GTPases, which comprise over 200 proteins, are expressed selectively in all cells, where they perform a range of cellular functions. A well-studied subfamily is that of the Rho GTPases, with the three best-understood members being Rho, Rac and cdc42. These molecules, including three isoforms of Rac, a number of Rho proteins and cdc42, a single gene product, regulate cell proliferation, differentiation, survival and many aspects of the cytoskeleton. We find cdc42 a particularly important regulator of osteoclast (OC) number and function. While increased cdc42 activity causes osteoporosis in mice, animals lacking the active GTPase specifically in their OCs have enhanced bone mass. Thus, cdc42 is a candidate therapeutic target for states of accelerated bone resorption. cdc42 deletion in OCs enhances their number by suppressing apoptosis, a process accompanied by increased amounts of the proapoptotic protein Bim. However, the impact of osteoclastic Bim on cell number and resorptive capacity in the context of cdc42 presence or absence is unknown. Moreover, Bim is also expressed in osteoblasts (OBs), where it regulates their lifespan and function. Finally, while Bim structure/function studies have been performed in a number of cell types, the residues that control OC and OB apoptosis are unknown. Based on these facts we hypothesize that: 1) absence of cdc42 in OCs arrests pathological bone loss;2) cdc42 and Bim act in concert in OCs to regulate apoptosis of bone resorptive cells, while Bim controls the OB and 3) specific residues in Bim govern its capacity to regulate OC and OB apoptosis. Given that we have generated mice with gain or loss of cdc42 function in OCs and have the capacity to selectively delete Bim in OCs or OBs in vivo, we are positioned to address the following specific aims: 1) determine the role of osteoclastic cdc42 in pathological bone loss, 2) determine how cdc42 and Bim, expressed in OCs and OBs, regulate apoptosis and bone mass in resorptive cells and 3) identify the specific residues in Bim that govern its capacity to regulate OC and OB apoptosis.
Bone mass reflects the balance between the cells that synthesize bone (osteoblasts) and those that degrade the tissue (osteoclasts). We have identified molecules in both cell types that control their rate of death. We propose a series of experiments that will determine the influence of these molecules in models of postmenopausal osteoporosis and arthritis, two common afflictions involving increased bone loss. These studies may identify novel targets for amelioration of these and related diseases.
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