| First Author | Vasheghani F | Year | 2015 |
| Journal | Ann Rheum Dis | Volume | 74 |
| Issue | 3 | Pages | 569-78 |
| PubMed ID | 25573665 | Mgi Jnum | J:342284 |
| Mgi Id | MGI:6780556 | Doi | 10.1136/annrheumdis-2014-205743 |
| Citation | Vasheghani F, et al. (2015) PPARgamma deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage. Ann Rheum Dis 74(3):569-78 |
| abstractText | OBJECTIVES: We have previously shown that peroxisome proliferator-activated receptor gamma (PPARgamma), a transcription factor, is essential for the normal growth and development of cartilage. In the present study, we created inducible cartilage-specific PPARgamma 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 PPARgamma in OA pathophysiology. We further investigated the downstream PPARgamma signalling pathway responsible for maintaining cartilage homeostasis. METHODS: Inducible cartilage-specific PPARgamma KO mice were generated and subjected to DMM model of OA. We also created inducible cartilage-specific PPARgamma/mammalian target for rapamycin (mTOR) double KO mice to dissect the PPARgamma signalling pathway in OA. RESULTS: Compared with control mice, PPARgamma 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 PPARgamma expression vector reduced mTOR expression, increased expression of autophagy markers and reduced the expression of OA inflammatory/catabolic factors, thus reversing the phenotype of PPARgamma KO mice chondrocytes. To dissect the in vivo role of mTOR pathway in PPARgamma signalling, we created and subjected PPARgamma-mTOR double KO mice to the OA model to see if the genetic deletion of mTOR in PPARgamma KO mice (double KO) can rescue the accelerated OA phenotype observed in PPARgamma KO mice. Indeed, PPARgamma-mTOR double KO mice exhibit significant protection/reversal from OA phenotype. SIGNIFICANCE: PPARgamma maintains articular cartilage homeostasis, in part, by regulating mTOR pathway. |
