title: Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis.
abstract: OBJECTIVE
  Mammalian target of rapamycin (mTOR) (a serine/threonine protein kinase) is a major repressor of autophagy, a cell survival mechanism. The specific in vivo mechanism of mTOR signalling in OA pathophysiology is not fully characterised. We determined the expression of mTOR and known autophagy genes in human OA cartilage as well as mouse and dog models of experimental OA. We created cartilage-specific mTOR knockout (KO) mice to determine the specific role of mTOR in OA pathophysiology and autophagy signalling in vivo.
  
  
  METHODS
  Inducible cartilage-specific mTOR KO mice were generated and subjected to mouse model of OA. Human OA chondrocytes were treated with rapamycin and transfected with Unc-51-like kinase 1 (ULK1) siRNA to determine mTOR signalling.
  
  
  RESULTS
  mTOR is overexpressed in human OA cartilage as well as mouse and dog experimental OA. Upregulation of mTOR expression co-relates with increased chondrocyte apoptosis and reduced expression of key autophagy genes during OA. Subsequently, we show for the first time that cartilage-specific ablation of mTOR results in increased autophagy signalling and a significant protection from destabilisation of medial meniscus (DMM)-induced OA associated with a significant reduction in the articular cartilage degradation, apoptosis and synovial fibrosis. Furthermore, we show that regulation of ULK1/adenosine monophosphate-activated protein kinase (AMPK) signalling pathway by mTOR may in part be responsible for regulating autophagy signalling and the balance between catabolic and anabolic factors in the articular cartilage.
  
  
  CONCLUSIONS
  This study provides a direct evidence of the role of mTOR and its downstream modulation of autophagy in articular cartilage homeostasis.
authors.affiliation: Osteoarthritis Research Unit, University of Montreal Research Centre (CRCHUM), Montreal, Quebec, Canada.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Osteoarthritis Research Unit, University of Montreal Research Centre (CRCHUM), Montreal, Quebec, Canada.
authors.forename: Faezeh
authors.initials: F
authors.lastname: Vasheghani
authors.affiliation: Osteoarthritis Research Unit, University of Montreal Research Centre (CRCHUM), Montreal, Quebec, Canada.
authors.forename: Ying-Hua
authors.initials: YH
authors.lastname: Li
authors.affiliation: Osteoarthritis Research Unit, University of Montreal Research Centre (CRCHUM), Montreal, Quebec, Canada.
authors.forename: Meryem
authors.initials: M
authors.lastname: Blati
authors.affiliation: Osteoarthritis Research Unit, University of Montreal Research Centre (CRCHUM), Montreal, Quebec, Canada.
authors.forename: Kayla
authors.initials: K
authors.lastname: Simeone
authors.affiliation: Osteoarthritis Research Unit, University of Montreal Research Centre (CRCHUM), Montreal, Quebec, Canada.
authors.forename: Hassan
authors.initials: H
authors.lastname: Fahmi
authors.affiliation: Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Lussier
authors.affiliation: Genetics Unit, Shriners Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Roughley
authors.affiliation: Pulmonary and Critical Care Unit and Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Massachusetts, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lagares
authors.affiliation: Osteoarthritis Research Unit, University of Montreal Research Centre (CRCHUM), Montreal, Quebec, Canada.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pelletier
authors.affiliation: Osteoarthritis Research Unit, University of Montreal Research Centre (CRCHUM), Montreal, Quebec, Canada.
authors.forename: Johanne
authors.initials: J
authors.lastname: Martel-Pelletier
authors.affiliation: Osteoarthritis Research Unit, University of Montreal Research Centre (CRCHUM), Montreal, Quebec, Canada Division of Genetics and Development, The Toronto Western Research Institute, Toronto Western Hospital, The University Health Network (UHN), Toronto, Ontario, Canada.
authors.forename: Mohit
authors.initials: M
authors.lastname: Kapoor
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology*; D000071189:Autophagy-Related Protein-1 Homolog; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004285:Dogs; D020868:Gene Silencing; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000172:deficiency* / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C484754:ULK1 protein, human; D055372:AMP-Activated Protein Kinases; D053509:Matrix Metalloproteinase 13; D020123:Sirolimus
keywords: Arthritis; Chondrocytes; Osteoarthritis