RT Journal Article
SR Electronic
T1 PPARγ deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 569
OP 578
DO 10.1136/annrheumdis-2014-205743
VO 74
IS 3
A1 Vasheghani, Faezeh
A1 Zhang, Yue
A1 Li, Ying-Hua
A1 Blati, Meryem
A1 Fahmi, Hassan
A1 Lussier, Bertrand
A1 Roughley, Peter
A1 Lagares, David
A1 Endisha, Helal
A1 Saffar, Bahareh
A1 Lajeunesse, Daniel
A1 Marshall, Wayne K
A1 Rampersaud, Y Raja
A1 Mahomed, Nizar N
A1 Gandhi, Rajiv
A1 Pelletier, Jean-Pierre
A1 Martel-Pelletier, Johanne
A1 Kapoor, Mohit
YR 2015
UL http://ard.bmj.com/content/74/3/569.abstract
AB 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.