CDC 42 BIM AND THE OSTEOCLAST

Ras小gtpase超家族的各种成员，包括200多种蛋白质，在所有细胞中选择性表达，并在细胞中执行一系列细胞功能。一个研究得很好的亚家族是Rho GTPases，其中三个最清楚的成员是Rho， Rac和cdc42。这些分子包括Rac的三种同工异构体、一些Rho蛋白和cdc42（一种单基因产物），它们调节细胞增殖、分化、存活和细胞骨架的许多方面。我们发现cdc42是一个特别重要的破骨细胞（OC）数量和功能的调节剂。而cdc42活性增加导致

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.