title: mTORC1 activation downregulates FGFR3 and PTH/PTHrP receptor in articular chondrocytes to initiate osteoarthritis.
abstract: Articular chondrocyte activation, involving aberrant proliferation and prehypertrophic differentiation, is essential for osteoarthritis (OA) initiation and progression. Disruption of mechanistic target of rapamycin complex 1 (mTORC1) promotes chondrocyte autophagy and survival, and decreases the severity of experimental OA. However, the role of cartilage mTORC1 activation in OA initiation is unknown. In this study, we elucidated the specific role of mTORC1 activation in OA initiation, and identify the underlying mechanisms.
  
  
  
  Expression of mTORC1 in articular cartilage of OA patients and OA mice was assessed by immunostaining. Cartilage-specific tuberous sclerosis complex 1 (Tsc1, mTORC1 upstream inhibitor) knockout (TSC1CKO) and inducible Tsc1 KO (TSC1CKOER) mice were generated. The functional effects of mTORC1 in OA initiation and development on its downstream targets were examined by immunostaining, western blotting and qPCR.
  
  
  
  Articular chondrocyte mTORC1 was activated in early-stage OA and in aged mice. TSC1CKO mice exhibited spontaneous OA, and TSC1CKOERmice (from 2 months) exhibited accelerated age-related and DMM-induced OA phenotypes, with aberrant chondrocyte proliferation and hypertrophic differentiation. This was associated with hyperactivation of mTORC1 and dramatic downregulation of FGFR3 and PPR, two receptors critical for preventing chondrocyte proliferation and differentiation. Rapamycin treatment reversed these phenotypes in KO mice. Furthermore, in vitro rescue experiments demonstrated that p73 and ERK1/2 may mediate the negative regulation of FGFR3 and PPR by mTORC1.
  
  
  
  mTORC1 activation stimulates articular chondrocyte proliferation and differentiation to initiate OA, in part by downregulating FGFR3 and PPR.
authors.affiliation: Academy of Orthopedics, Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China. Electronic address: zhhy0704@126.com.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Key Laboratory of Tropical Diseases and Translational Medicine of the Ministry of Education, Hainan Medical College, Haikou, China. Electronic address: wanghua8031@126.com.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.affiliation: Academy of Orthopedics, Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China. Electronic address: zengdavid@126.com.
authors.forename: C
authors.initials: C
authors.lastname: Zeng
authors.affiliation: Academy of Orthopedics, Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China. Electronic address: yanbosmu@gmail.com.
authors.forename: B
authors.initials: B
authors.lastname: Yan
authors.affiliation: Academy of Orthopedics, Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China. Electronic address: oyjysmu029@126.com.
authors.forename: J
authors.initials: J
authors.lastname: Ouyang
authors.affiliation: Academy of Orthopedics, Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China. Electronic address: liuxin_smu@sina.com.
authors.forename: X
authors.initials: X
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, China. Electronic address: Sunqiuyi2355287@163.com.
authors.forename: Q
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Academy of Orthopedics, Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China. Electronic address: zhaochang81@126.com.
authors.forename: C
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Academy of Orthopedics, Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China. Electronic address: fanghang@outlook.com.
authors.forename: H
authors.initials: H
authors.lastname: Fang
authors.affiliation: Academy of Orthopedics, Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China. Electronic address: storm0132002@163.com.
authors.forename: J
authors.initials: J
authors.lastname: Pan
authors.affiliation: Academy of Orthopedics, Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China. Electronic address: ste.ven.06@163.com.
authors.forename: D
authors.initials: D
authors.lastname: Xie
authors.affiliation: Academy of Orthopedics, General Hospital of Guangzhou Military Command of PLA, Guangzhou, China. Electronic address: gdgkyjc@126.com.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: Academy of Orthopedics, General Hospital of Guangzhou Military Command of PLA, Guangzhou, China. Electronic address: gzlupus@126.com.
authors.forename: T
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Academy of Orthopedics, Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China; State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China. Electronic address: baixc15@smu.edu.cn.
authors.forename: X
authors.initials: X
authors.lastname: Bai
authors.affiliation: Academy of Orthopedics, Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China. Electronic address: daozhang@medmail.com.cn.
authors.forename: D
authors.initials: D
authors.lastname: Cai
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002082:Butylamines / Q000494:pharmacology; D002358:Cartilage, Articular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation / Q000235:genetics; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D006984:Hypertrophy; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007719:Knee Joint / Q000187:drug effects / Q000473:pathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism*; D008592:Menisci, Tibial / Q000601:surgery; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D010003:Osteoarthritis / Q000235:genetics* / Q000378:metabolism; D020370:Osteoarthritis, Knee / Q000378:metabolism*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000187:drug effects / Q000378:metabolism; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: C121358:4-phenylbutylamine; D002082:Butylamines; D007166:Immunosuppressive Agents; D044168:Receptor, Parathyroid Hormone, Type 1; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C546843:mTOR protein, mouse; C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Chondrocyte; FGFR3; Osteoarthritis; PPR; mTORC1