TGF BETA Regulation of Osteoclast Apoptosis

描述（由申请人提供）：牙周炎是一种慢性炎症性疾病，导致破骨细胞介导的骨破坏，导致牙齿脱落。细胞因子tgf - β最初促进炎症反应，但最终通过抑制骨降解来减缓骨质流失。根据已发表的报告和我们的初步数据，这种抑制的一个重要组成部分似乎是破骨细胞凋亡的开始。通过靶向破骨细胞存活途径减少破骨细胞数量可能为减缓牙周炎、骨质疏松和肿瘤驱动的骨溶解期间的病理性骨质流失提供重要的未来治疗靶点。本研究的目的是明确TGF- β调控破骨细胞凋亡的分子通路。在初步研究中，我们观察到(i)破骨细胞的存活是由于MEK/ERK和AKT/NF(B)存活通路的持续激活；（ii） PI3K协同激活这些通路以促进破骨细胞的存活；（iii） tgf - β通过抑制这些存活途径诱导破骨细胞凋亡。这些数据导致了我们的中心假设，纯化的破骨细胞存活是由于激活存活途径，而TGF-a抑制存活途径以提高破骨细胞凋亡。为了验证我们的假设，本提案的目的是：

DESCRIPTION (provided by applicant): Periodontitis is a chronic inflammatory disease that leads to osteoclast-mediated bone destruction, resulting in tooth loss. The cytokine TGF-beta initially promotes the inflammatory response, but ultimately slows bone loss by suppressing bone degradation. On the basis of published reports and our preliminary data, it appears likely that an important component of this repression is the initiation of osteoclast apoptosis. Reducing osteoclast numbers through targeting osteoclast survival pathways may provide important future therapeutic targets to slow pathological bone loss during periodontitis, osteoporosis, and tumor-driven osteolysis. It is the goal of this research to define the molecular pathways linking TGF- beta to regulation of osteoclast apoptosis. In preliminary studies, we observed that (i) osteoclast survival is due to continual activation of the MEK/ERK and AKT/NF(B survival pathways; (ii) PI3K coordinately activates these pathways to promote osteoclast survival; and (iii) TGF-beta induces apoptosis in surviving osteoclasts by repression of these survival pathways. These data have led to our central hypothesis that purified osteoclasts survive due to activation of survival pathways while TGF-a suppresses survival pathways to elevate osteoclast apoptosis. To test our hypothesis, the Aims of this proposal are to: (1) resolve the role of the MEK/ERK pathway in osteoclast survival. (2) establish the role of the AKT/NFkappaB pathway in osteoclast survival. (3) elucidate the cross-talk between the AKT/NFkappaB and MEK/ERK pathways in promoting osteoclast survival. (4) determine the mechanisms by which TGF-beta targets survival-promoting signaling pathways to induce osteoclast apoptosis. Understanding osteoclast apoptosis regulation may provide important avenues for therapies to slow bone degradation during pathological bone loss.