ATF-4, A Novel Mediator of the Anabolic Actions of PTH on Bone

摘要

In this study, we have successfully demonstrated that ATF4 plays a critical role in mediating the anabolic effects of intermittent PTH on bones. ATF4 is important for intermittent PTH to stimulate bone formation in mice. ATF4 favors bone formation through, at least in part, upregulation of osteoblasst proliferation and survival. Additionally, ATF4 increases osteoblast differentiation probably via osterix. At molecular level, ATF4 increases osteocalcin gene expression by cooperative interactions with TFIIA and Runx2. ATF4 increases the expression of cyclin D1, a key factor for cell cycle progression. We have identified and functionally characterized Erk/MAPK phosphorylation sites in Runx2, an ATF4-interacting factor. We have demonstrated that ATF4 is essential for osteoclast differentiation and bone resorption, which is increased by intermittent PTH.