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

Objectives We have previously shown that peroxisome proliferator-activated receptor gamma (PPAR gamma), a transcription factor, is essential for the normal growth and development of cartilage. In the present study, we created inducible cartilage-specific PPAR gamma 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 PPAR gamma in OA pathophysiology. We further investigated the downstream PPAR gamma signalling pathway responsible for maintaining cartilage homeostasis. Methods Inducible cartilage-specific PPAR gamma KO mice were generated and subjected to DMM model of OA. We also created inducible cartilage-specific PPAR gamma/mammalian target for rapamycin (mTOR) double KO mice to dissect the PPAR gamma signalling pathway in OA. Results Compared with control mice, PPAR gamma 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 PPAR gamma expression vector reduced mTOR expression, increased expression of autophagy markers and reduced the expression of OA inflammatory/catabolic factors, thus reversing the phenotype of PPAR gamma KO mice chondrocytes. To dissect the in vivo role of mTOR pathway in PPAR gamma signalling, we created and subjected PPAR gamma-mTOR double KO mice to the OA model to see if the genetic deletion of mTOR in PPAR gamma KO mice (double KO) can rescue the accelerated OA phenotype observed in PPAR gamma KO mice. Indeed, PPAR gamma-mTOR double KO mice exhibit significant protection/reversal from OA phenotype. Significance PPAR gamma maintains articular cartilage homeostasis, in part, by regulating mTOR pathway.