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Ann Rheum Dis. 2015 Mar;74(3):569-78. doi: 10.1136/annrheumdis-2014-205743. Epub 2015 Jan 8.

PPARγ deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage.

Author information

1
Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Montreal, Quebec, Canada.
2
Division of Genetics and Development, Toronto Western Research Institute, University Health Network (UHN), Toronto, Ontario, Canada.
3
Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Montreal, St-Hyacinthe, Quebec, Canada.
4
Genetics Unit, Shriners Hospital, McGill University, Montreal, Quebec, Canada.
5
Pulmonary and Critical Care Unit and Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Massachusetts, USA.
6
Division of Orthopedics, Toronto Western Hospital, Toronto, Ontario, Canada.
7
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.

Abstract

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.

KEYWORDS:

Arthritis; Chondrocytes; Osteoarthritis

PMID:
25573665
PMCID:
PMC4345902
DOI:
10.1136/annrheumdis-2014-205743
[Indexed for MEDLINE]
Free PMC Article

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