Peroxisome proliferator activated receptor alpha activation decreases inflammatory and destructive responses in osteoarthritic cartilage

Objective: Peroxisome proliferator activated receptor alpha (PPAR alpha) agonists are used in clinical practice as lipid-lowering drugs and are also known to exert anti-inflammatory effects on various tissues. We hypothesized that PPAR alpha activation leads to anti-inflammatory and anti-destructive effects in human OA cartilage. Methods: Cartilage explants obtained from six OA patients were cultured for 48 h with 10 ng/ml interleukin (IL)1 beta as a pro-inflammatory stimulus. 100 mu M Wy-14643, a potent and selective PPAR alpha agonist, was added to the cultures and gene expression of matrix metalloproteinase (MMP)1, MMP3, MMP13, collagen type II (COL2A1), aggrecan and PPAR alpha in cartilage explants and the release of glycosaminoglycans (GAGs), nitric oxide (NO) and prostaglandin E(2)(PGE(2)) in the culture media were analyzed and compared to the control without Wy-14643. Results: Addition of Wy-14643 decreased mRNA expression of MMP1, MMP3 and MMP13 in cartilage explants that responded to IL1 beta, whereas Wy-14643 did not affect gene expression of COL2A1 and aggrecan. Wy-14643 also decreased secretion of inflammatory marker NO in the culture medium of cartilage explants responding to IL1 beta. Wy-14643 inhibited the release of GAGs by cartilage explants in culture media. Conclusion: PPAR alpha agonist Wy-14643 inhibited the inflammatory and destructive responses in human OA cartilage explants and did not have an effect on COL2A1 or aggrecan mRNA expression. These effects of PPAR alpha agonists on osteoarthritic cartilage warrant further investigation of these drugs as a potential therapeutic strategy for osteoarthritis (OA). (C) 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.