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Extended report
Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis
  1. Yue Zhang1,
  2. Faezeh Vasheghani1,
  3. Ying-hua Li1,
  4. Meryem Blati1,
  5. Kayla Simeone1,
  6. Hassan Fahmi1,
  7. Bertrand Lussier2,
  8. Peter Roughley3,
  9. David Lagares4,
  10. Jean-Pierre Pelletier1,
  11. Johanne Martel-Pelletier1,
  12. Mohit Kapoor1,5
  1. 1Osteoarthritis Research Unit, University of Montreal Research Centre (CRCHUM), Montreal, Quebec, Canada
  2. 2Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Montreal, Montreal, Quebec, Canada
  3. 3Genetics Unit, Shriners Hospital, McGill University, Montreal, Quebec, Canada
  4. 4Pulmonary and Critical Care Unit and Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Massachusetts, USA
  5. 5Division of Genetics and Development, The Toronto Western Research Institute, Toronto Western Hospital, The University Health Network (UHN), Toronto, Ontario, Canada
  1. Correspondence to Dr Mohit Kapoor, Division of Genetics and Development, The Toronto Western Research Institute, Toronto Western Hospital, The University Health Network (UHN), 60 Leonard Avenue, Toronto, Ontario, Canada M5T 2S8; mkapoor{at}uhnresearch.ca

Abstract

Objectives 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.

  • Osteoarthritis
  • Chondrocytes
  • Arthritis

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