Peroxisome proliferator-activated receptor γ1 expression is diminished in human osteoarthritic cartilage and is downregulated by interleukin-1β in articular chondrocytes

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor involved in the regulation of many cellular processes. We and others have previously shown that PPAR gamma activators display anti-inflammatory and chondroprotective properties in vitro and improve the clinical course and histopathological features in an experimental animal model of osteoarthritis (OA). However, the expression and regulation of PPAR gamma expression in cartilage are poorly defined. This study was undertaken to investigate the quantitative expression and distribution of PPAR gamma in normal and OA cartilage and to evaluate the effect of IL-1 beta, a prominent cytokine in OA, on PPAR gamma expression in cultured chondrocytes. Immunohistochemical analysis revealed that the levels of PPAR gamma protein expression were significantly lower in OA cartilage than in normal cartilage. Using real-time RT-PCR, we demonstrated that PPAR gamma 1 mRNA levels were about 10-fold higher than PPAR gamma 2 mRNA levels, and that only PPAR gamma 1 was differentially expressed: its levels in OA cartilage was 2.4-fold lower than in normal cartilage (p < 0.001). IL-1 treatment of OA chondrocytes downregulated PPAR gamma 1 expression in a dose- and time-dependent manner. This effect probably occurred at the transcriptional level, because IL-1 decreases both PPAR gamma 1 mRNA expression and PPAR gamma 1 promoter activity. TNF-alpha, IL-17, and prostaglandin E-2 (PGE(2)), which are involved in the pathogenesis of OA, also downregulated PPAR gamma 1 expression. Specific inhibitors of the mitogen-activated protein kinases (MAPKs) p38 (SB203580) and c-Jun N-terminal kinase (SP600125), but not of extracellular signal-regulated kinase (PD98059), prevented IL-1-induced downregulation of PPAR gamma 1 expression. Similarly, inhibitors of NF-kappa B signaling (pyrrolidine dithiocarbamate, MG-132, and SN-50) abolished the suppressive effect of IL-1. Thus, our study demonstrated that PPAR gamma 1 is downregulated in OA cartilage. The pro-inflammatory cytokine IL-1 may be responsible for this downregulation via a mechanism involving activation of the MAPKs (p38 and JNK) and NF-kappa B signaling pathways. The IL-1-induced downregulation of PPAR gamma expression might be a new and additional important process by which IL-1 promotes articular inflammation and cartilage degradation.