TGF BETA Regulation of Osteoclast Apoptosis

Project: Research project

Project Details


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.
StatusNot started


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