title: Enhancement of the synthesis of n-3 PUFAs in fat-1 transgenic mice inhibits mTORC1 signalling and delays surgically induced osteoarthritis in comparison with wild-type mice.
abstract: BACKGROUND
  An exogenous supplement of n-3 polyunsaturated fatty acids (PUFAs) has been reported to prevent osteoarthritis (OA) through undefined mechanisms.
  
  
  OBJECTIVE
  This study investigated the effect of alterations in the composition of endogenous PUFAs on OA, and associations of PUFAs with mammalian target of rapamycin complex 1 (mTORC1) signalling, a critical autophagy pathway in fat-1 transgenic (TG) mice.
  
  
  METHODS
  fat-1 TG and wild-type mice were used to create an OA model by resecting the medial meniscus. The composition of the endogenous PUFAs in mouse tissues was analysed by gas chromatography, and the incidence of OA was evaluated by micro-computed tomography (micro-CT), scanning electron microscopy and histological methods. Additionally, primary chondrocytes were isolated and cultured. The effect of exogenous and endogenous PUFAs on mTORC1 activity and autophagy in chondrocytes was assessed.
  
  
  RESULTS
  The composition of endogenous PUFAs of TG mice was optimised both by increased n-3 PUFAs and decreased n-6 PUFAs, which significantly alleviated the articular cartilage destruction and osteophytosis in the OA model (p<0.01), decreased protein expression of matrix metalloproteinase-13 (MMP-13) and ADAMTS-5 (a disintegrin and metalloproteinase with thrombospondin motifs) in the articular cartilage (p<0.01) and reduced chondrocyte number and loss of cartilage extracellular matrix. Both exogenous and endogenous n-3 PUFAs downregulated mTORC1 activity and promoted autophagy in articular chondrocytes. Conversely, mTORC1 pathway activation suppressed autophagy in articular chondrocytes.
  
  
  CONCLUSIONS
  Enhancement of the synthesis of endogenous n-3 PUFAs from n-6 PUFAs can delay the incidence of OA, probably through inhibition of mTORC1, promotion of autophagy and cell survival in cartilage chondrocytes. Future investigation into the role of the endogenous n-6/n-3 PUFAs composition in OA prevention and treatment is warranted.
authors.affiliation: Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, PR China Academy of Orthopedics, Guangdong Province, Guangzhou, Guangdong, PR China.
authors.forename: Min-Jun
authors.initials: MJ
authors.lastname: Huang
authors.affiliation: Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, PR China Academy of Orthopedics, Guangdong Province, Guangzhou, Guangdong, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, PR China Academy of Orthopedics, Guangdong Province, Guangzhou, Guangdong, PR China.
authors.forename: Da-di
authors.initials: DD
authors.lastname: Jin
authors.affiliation: Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, PR China Academy of Orthopedics, Guangdong Province, Guangzhou, Guangdong, PR China.
authors.forename: Zhong-Min
authors.initials: ZM
authors.lastname: Zhang
authors.affiliation: Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, PR China Academy of Orthopedics, Guangdong Province, Guangzhou, Guangdong, PR China.
authors.forename: Tian-Yu
authors.initials: TY
authors.lastname: Chen
authors.affiliation: Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, Guangdong, PR China.
authors.forename: Chun-Hong
authors.initials: CH
authors.lastname: Jia
authors.affiliation: The Center of Metabolic Disease Research, Nanjing Medical University, Nanjing, Jiangsu, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, PR China Academy of Orthopedics, Guangdong Province, Guangzhou, Guangdong, PR China.
authors.forename: Xiao-Chen
authors.initials: XC
authors.lastname: Zhen
authors.affiliation: Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, PR China Academy of Orthopedics, Guangdong Province, Guangzhou, Guangdong, PR China.
authors.forename: Bin
authors.initials: B
authors.lastname: Huang
authors.affiliation: Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, PR China Academy of Orthopedics, Guangdong Province, Guangzhou, Guangdong, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yan
authors.affiliation: Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, PR China Academy of Orthopedics, Guangdong Province, Guangzhou, Guangdong, PR China.
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, PR China Academy of Orthopedics, Guangdong Province, Guangzhou, Guangdong, PR China.
authors.forename: Sheng-Fa
authors.initials: SF
authors.lastname: Li
authors.affiliation: Department of Orthopedics, Liu Hua Qiao Hospital, Guangzhou, Guangdong, PR China.
authors.forename: Jin-Cheng
authors.initials: JC
authors.lastname: Yang
authors.affiliation: The Center of Metabolic Disease Research, Nanjing Medical University, Nanjing, Jiangsu, PR China.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Dai
authors.affiliation: Academy of Orthopedics, Guangdong Province, Guangzhou, Guangdong, PR China Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, Guangdong, PR China.
authors.forename: Xiao-Chun
authors.initials: XC
authors.lastname: Bai
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000071116:ADAMTS5 Protein; D000818:Animals; D001169:Arthritis, Experimental / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D001343:Autophagy / Q000502:physiology; D015820:Cadherins / Q000235:genetics; D002358:Cartilage, Articular / Q000378:metabolism / Q000648:ultrastructure; D019902:Chondrocytes / Q000473:pathology; D018450:Disease Progression; D015525:Fatty Acids, Omega-3 / Q000096:biosynthesis* / Q000502:physiology; D043371:Fatty Acids, Omega-6 / Q000096:biosynthesis; D005260:Female; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008855:Microscopy, Electron, Scanning; D046912:Multiprotein Complexes / Q000502:physiology*; D010003:Osteoarthritis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D011509:Proteoglycans / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D015820:Cadherins; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D046912:Multiprotein Complexes; D011509:Proteoglycans; C502406:fat1 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C498489:Adamts5 protein, mouse; D053509:Matrix Metalloproteinase 13
keywords: Chondrocytes; Cytokines; Inflammation; Osteoarthritis