mTORC1 regulates PTHrP to coordinate chondrocyte growth, proliferation and differentiation.
mTORC1 regulates PTHrP to coordinate chondrocyte growth, proliferation and differentiation.
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mTORC1 调节 PTHrP 协调软骨细胞生长、增殖和分化
DOI：
10.1038/ncomms11151
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发表时间：
2016-04-04
影响因子：
16.6
通讯作者：
Bai X
中科院分区：
文献类型：
--
作者：
Yan B;Zhang Z;Jin D;Cai C;Jia C;Liu W;Wang T;Li S;Zhang H;Huang B;Lai P;Wang H;Liu A;Zeng C;Cai D;Jiang Y;Bai X
细胞生长、增殖和分化的精确协调对多细胞生物的发育至关重要。在这里，我们报道，尽管雷帕霉素复合物1 （mTORC1）活性的机制靶点是软骨细胞生长和增殖所必需的，但其失活对软骨细胞分化至关重要。软骨细胞中mTORC1通过atsc1基因缺失的过度激活导致生长板内正常增殖和分化程序的解偶联，导致细胞增殖失控，阻断小鼠分化和软骨发育不良。雷帕霉素促进突变小鼠的软骨细胞分化并恢复这些缺陷。从机制上说，mTORC1下游激酶S6K1与Gli2相互作用并磷酸化Gli2，并通过SuFu结合释放Gli2，导致Gli2的核易位和骨发育的关键调节因子甲状旁腺激素相关肽（PTHrP）的转录。我们的研究结果表明，动态控制mTORC1活性对协调软骨细胞增殖和分化至关重要，部分通过调节软骨内骨发育过程中的Gli2/PTHrP。
Precise coordination of cell growth, proliferation and differentiation is essential for the development of multicellular organisms. Here, we report that although the mechanistic target of rapamycin complex 1 (mTORC1) activity is required for chondrocyte growth and proliferation, its inactivation is essential for chondrocyte differentiation. Hyperactivation of mTORC1 viaTSC1gene deletion in chondrocytes causes uncoupling of the normal proliferation and differentiation programme within the growth plate, resulting in uncontrolled cell proliferation, and blockage of differentiation and chondrodysplasia in mice. Rapamycin promotes chondrocyte differentiation and restores these defects in mutant mice. Mechanistically, mTORC1 downstream kinase S6K1 interacts with and phosphorylates Gli2, and releases Gli2 from SuFu binding, resulting in nuclear translocation of Gli2 and transcription of parathyroid hormone-related peptide (PTHrP), a key regulator of bone development. Our findings demonstrate that dynamically controlled mTORC1 activity is crucial to coordinate chondrocyte proliferation and differentiation partially through regulating Gli2/PTHrP during endochondral bone development.