mTORC1 regulates PTHrP to coordinate chondrocyte growth, proliferation and differentiation

Bo Yan, Zhongmin Zhang, Dadi Jin, Chen Cai, Chunhong Jia, Wen Liu, Ting Wang, Shengfa Li, Haiyan Zhang, Bin Huang, Pinglin Lai, Hua Wang, Anling Liu, Chun Zeng, Daozhang Cai, Yu Jiang and Xiaochun Bai ()
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Bo Yan: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University
Zhongmin Zhang: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University
Dadi Jin: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University
Chen Cai: Zhujiang Hospital, Southern Medical University
Chunhong Jia: State Key Laboratory of Organ Failure Research, School of Basic Medical Sciences, Southern Medical University
Wen Liu: State Key Laboratory of Organ Failure Research, School of Basic Medical Sciences, Southern Medical University
Ting Wang: State Key Laboratory of Organ Failure Research, School of Basic Medical Sciences, Southern Medical University
Shengfa Li: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University
Haiyan Zhang: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University
Bin Huang: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University
Pinglin Lai: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University
Hua Wang: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University
Anling Liu: State Key Laboratory of Organ Failure Research, School of Basic Medical Sciences, Southern Medical University
Chun Zeng: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University
Daozhang Cai: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University
Yu Jiang: University of Pittsburgh School of Medicine
Xiaochun Bai: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: Abstract 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 via TSC1 gene 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.

Date: 2016
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DOI: 10.1038/ncomms11151

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