title: mTORC1 regulates PTHrP to coordinate chondrocyte growth, proliferation and differentiation.
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.
authors.affiliation: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yan
authors.affiliation: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China.
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China.
authors.forename: Dadi
authors.initials: D
authors.lastname: Jin
authors.affiliation: Department of Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Jia
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China.
authors.forename: Shengfa
authors.initials: S
authors.lastname: Li
authors.affiliation: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Huang
authors.affiliation: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China.|State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Pinglin
authors.initials: P
authors.lastname: Lai
authors.affiliation: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China.|State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Anling
authors.initials: A
authors.lastname: Liu
authors.affiliation: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Zeng
authors.affiliation: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China.
authors.forename: Daozhang
authors.initials: D
authors.lastname: Cai
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China.|State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Bai
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049108:Cell Enlargement; D049109:Cell Proliferation; D019902:Chondrocytes / Q000166:cytology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D046912:Multiprotein Complexes; D044162:Parathyroid Hormone-Related Protein; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases