CDC 42 BIM AND THE OSTEOCLAST

小 GTP 酶 Ras 超家族的各个成员包含 200 多种蛋白质，在所有细胞中选择性表达，并在其中执行一系列细胞功能。 Rho GTPases 是一个经过充分研究的亚家族，其中三个最了解的成员是 Rho、Rac 和 cdc42。这些分子包括 Rac 的三种亚型、多种 Rho 蛋白和单基因产物 cdc42，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 是破骨细胞 (OC) 数量和功能特别重要的调节因子。虽然 cdc42 活性增加会导致 在患有骨质疏松症的小鼠中，特别是在其 OC 中缺乏活性 GTP 酶的动物的骨量有所增加。因此，cdc42是加速骨吸收状态的候选治疗靶点。 OC 中 cdc42 的缺失通过抑制细胞凋亡来增加其数量，这一过程伴随着促凋亡蛋白 Bim 数量的增加。然而，在 cdc42 存在或不存在的情况下，破骨细胞 Bim 对细胞数量和吸收能力的影响尚不清楚。此外，Bim也在成骨细胞（OBs）中表达， 它调节它们的寿命和功能。最后，虽然 Bim 结构/功能研究已在多种细胞类型中进行，但控制 OC 和 OB 细胞凋亡的残基尚不清楚。基于这些事实，我们假设：1）OC 中 cdc42 的缺失可阻止病理性骨丢失； 2) cdc42 和 Bim 在 OC 中协同作用，调节骨吸收细胞的凋亡，而 Bim 控制 OB，3) Bim 中的特定残基控制其调节 OC 和 OB 凋亡的能力。鉴于我们已经培育出在 OC 中获得或丧失 cdc42 功能的小鼠，并且能够在体内选择性删除 OC 或 OB 中的 Bim，我们致力于解决以下具体目标：1）确定破骨细胞 cdc42 在病理性骨丢失中的作用，2）确定在 OC 和 OB 中表达的 cdc42 和 Bim 如何调节再吸收细胞中的细胞凋亡和骨量，3）识别 Bim 中的特定残基控制其调节 OC 和 OB 细胞凋亡的能力。

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.