Article Text

Extended report
PPARγ deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage
  1. Faezeh Vasheghani1,
  2. Yue Zhang2,
  3. Ying-Hua Li2,
  4. Meryem Blati1,
  5. Hassan Fahmi1,
  6. Bertrand Lussier3,
  7. Peter Roughley4,
  8. David Lagares5,
  9. Helal Endisha2,
  10. Bahareh Saffar2,
  11. Daniel Lajeunesse1,
  12. Wayne K Marshall6,
  13. Y Raja Rampersaud6,
  14. Nizar N Mahomed6,
  15. Rajiv Gandhi6,
  16. Jean-Pierre Pelletier1,
  17. Johanne Martel-Pelletier1,
  18. Mohit Kapoor1,2,6,7
  1. 1Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Montreal, Quebec, Canada
  2. 2Division of Genetics and Development, Toronto Western Research Institute, University Health Network (UHN), Toronto, Ontario, Canada
  3. 3Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Montreal, St-Hyacinthe, Quebec, Canada
  4. 4Genetics Unit, Shriners Hospital, McGill University, Montreal, Quebec, Canada
  5. 5Pulmonary and Critical Care Unit and Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Massachusetts, USA
  6. 6Division of Orthopedics, Toronto Western Hospital, Toronto, Ontario, Canada
  7. 7Department of Surgery, University of Toronto, Toronto, Ontario, Canada
  1. Correspondence to Dr Mohit Kapoor, The Toronto Western Research Institute, Toronto Western Hospital, The University Health Network (UHN), 60 Leonard Avenue, Toronto, Ontario, M5T 2S8, Canada; mkapoor{at}


Objectives 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.

Significance PPARγ maintains articular cartilage homeostasis, in part, by regulating mTOR pathway.

  • Osteoarthritis
  • Chondrocytes
  • Arthritis

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