mTORC1 Prevents Preosteoblast Differentiation through the Notch Signaling Pathway.
mTORC1 Prevents Preosteoblast Differentiation through the Notch Signaling Pathway.
复制标题
mTORC1 通过 Notch 信号通路阻止前成骨细胞分化
DOI：
10.1371/journal.pgen.1005426
复制
发表时间：
2015-08
期刊：
影响因子：
4.5
通讯作者：
Bai X
中科院分区：
文献类型：
--
作者：
Huang B;Wang Y;Wang W;Chen J;Lai P;Liu Z;Yan B;Xu S;Zhang Z;Zeng C;Rong L;Liu B;Cai D;Jin D;Bai X
雷帕霉素的机制靶标（mTOR）整合细胞内和细胞外信号以调节细胞生长和代谢。然而，mTOR信号传导在成骨细胞分化和骨形成中的作用尚不明确，其潜在机制尚未阐明。在这里，我们报告说，mTOR复合物1（mTORC 1）的激活是前成骨细胞增殖所必需的，然而，mTORC 1的失活是必不可少的分化和成熟。抑制mTORC 1阻止前成骨细胞增殖，但在体外和小鼠中增强其分化。通过在前成骨细胞中删除结节性硬化症1（Tsc 1）来激活mTORC 1，由于过度增殖但细胞的分化和成熟受损，在小鼠中产生不成熟的编织骨。mTORC 1特异性抑制剂雷帕霉素恢复了这些体外和体内表型变化。mTORC 1通过激活STAT 3/p63/Jagged/Notch通路和下调Runx 2阻止成骨细胞成熟。当抑制Notch通路时，具有过度活跃mTORC 1的前成骨细胞重新获得完全分化和成熟的能力。总之，这些发现确定了mTORC 1在成骨细胞形成中的作用，并确定mTORC 1通过激活Notch途径阻止前成骨细胞分化和成熟。
The mechanistic target of rapamycin (mTOR) integrates both intracellular and extracellular signals to regulate cell growth and metabolism. However, the role of mTOR signaling in osteoblast differentiation and bone formation is undefined, and the underlying mechanisms have not been elucidated. Here, we report that activation of mTOR complex 1 (mTORC1) is required for preosteoblast proliferation; however, inactivation of mTORC1 is essential for their differentiation and maturation. Inhibition of mTORC1 prevented preosteoblast proliferation, but enhanced their differentiation in vitro and in mice. Activation of mTORC1 by deletion of tuberous sclerosis 1 (Tsc1) in preosteoblasts produced immature woven bone in mice due to excess proliferation but impaired differentiation and maturation of the cells. The mTORC1-specific inhibitor, rapamycin, restored these in vitro and in vivo phenotypic changes. Mechanistically, mTORC1 prevented osteoblast maturation through activation of the STAT3/p63/Jagged/Notch pathway and downregulation of Runx2. Preosteoblasts with hyperactive mTORC1 reacquired the capacity to fully differentiate and maturate when subjected to inhibition of the Notch pathway. Together, these findings identified the role of mTORC1 in osteoblast formation and established that mTORC1 prevents preosteoblast differentiation and maturation through activation of the Notch pathway.