title: PPARγ deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage.
abstract: OBJECTIVE
  We have previously shown that peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor, is essential for the normal growth and development of cartilage. In the present study, we created inducible cartilage-specific PPARγ knockout (KO) mice and subjected these mice to the destabilisation of medial meniscus (DMM) model of osteoarthritis (OA) to elucidate the specific in vivo role of PPARγ in OA pathophysiology. We further investigated the downstream PPARγ signalling pathway responsible for maintaining cartilage homeostasis.
  
  
  METHODS
  Inducible cartilage-specific PPARγ KO mice were generated and subjected to DMM model of OA. We also created inducible cartilage-specific PPARγ/mammalian target for rapamycin (mTOR) double KO mice to dissect the PPARγ signalling pathway in OA.
  
  
  RESULTS
  Compared with control mice, PPARγ KO mice exhibit accelerated OA phenotype with increased cartilage degradation, chondrocyte apoptosis, and the overproduction of OA inflammatory/catabolic factors associated with the increased expression of mTOR and the suppression of key autophagy markers. In vitro rescue experiments using PPARγ expression vector reduced mTOR expression, increased expression of autophagy markers and reduced the expression of OA inflammatory/catabolic factors, thus reversing the phenotype of PPARγ KO mice chondrocytes. To dissect the in vivo role of mTOR pathway in PPARγ signalling, we created and subjected PPARγ-mTOR double KO mice to the OA model to see if the genetic deletion of mTOR in PPARγ KO mice (double KO) can rescue the accelerated OA phenotype observed in PPARγ KO mice. Indeed, PPARγ-mTOR double KO mice exhibit significant protection/reversal from OA phenotype.
  
  
  CONCLUSIONS
  PPARγ maintains articular cartilage homeostasis, in part, by regulating mTOR pathway.
authors.affiliation: Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Montreal, Quebec, Canada.
authors.forename: Faezeh
authors.initials: F
authors.lastname: Vasheghani
authors.affiliation: Division of Genetics and Development, Toronto Western Research Institute, University Health Network (UHN), Toronto, Ontario, Canada.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Genetics and Development, Toronto Western Research Institute, University Health Network (UHN), Toronto, Ontario, Canada.
authors.forename: Ying-Hua
authors.initials: YH
authors.lastname: Li
authors.affiliation: Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Montreal, Quebec, Canada.
authors.forename: Meryem
authors.initials: M
authors.lastname: Blati
authors.affiliation: Osteoarthritis Research Unit, University of Montreal Hospital 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, St-Hyacinthe, 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: Division of Genetics and Development, Toronto Western Research Institute, University Health Network (UHN), Toronto, Ontario, Canada.
authors.forename: Helal
authors.initials: H
authors.lastname: Endisha
authors.affiliation: Division of Genetics and Development, Toronto Western Research Institute, University Health Network (UHN), Toronto, Ontario, Canada.
authors.forename: Bahareh
authors.initials: B
authors.lastname: Saffar
authors.affiliation: Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Montreal, Quebec, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lajeunesse
authors.affiliation: Division of Orthopedics, Toronto Western Hospital, Toronto, Ontario, Canada.
authors.forename: Wayne K
authors.initials: WK
authors.lastname: Marshall
authors.affiliation: Division of Orthopedics, Toronto Western Hospital, Toronto, Ontario, Canada.
authors.forename: Y Raja
authors.initials: YR
authors.lastname: Rampersaud
authors.affiliation: Division of Orthopedics, Toronto Western Hospital, Toronto, Ontario, Canada.
authors.forename: Nizar N
authors.initials: NN
authors.lastname: Mahomed
authors.affiliation: Division of Orthopedics, Toronto Western Hospital, Toronto, Ontario, Canada.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Gandhi
authors.affiliation: Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Montreal, Quebec, Canada.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pelletier
authors.affiliation: Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Montreal, Quebec, Canada.
authors.forename: Johanne
authors.initials: J
authors.lastname: Martel-Pelletier
authors.affiliation: Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Montreal, Quebec, Canada Division of Genetics and Development, Toronto Western Research Institute, University Health Network (UHN), Toronto, Ontario, Canada Division of Orthopedics, Toronto Western Hospital, Toronto, Ontario, Canada Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mohit
authors.initials: M
authors.lastname: Kapoor
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism*; D004195:Disease Models, Animal; D008592:Menisci, Tibial / Q000601:surgery; D051379:Mice; D018345:Mice, Knockout; D020370:Osteoarthritis, Knee / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D047495:PPAR gamma; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: Arthritis; Chondrocytes; Osteoarthritis