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Peroxisome proliferator-activated receptor gamma 1 expression is diminished in human osteoarthritis cartilage and is downregulated by IL-1β in articular chondrocytes

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Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor involved in the regulation of many cellular processes. We and others have previously shown that PPARγ 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 PPARγ expression in cartilage are poorly defined. This study was undertaken to investigate the quantitative expression and distribution of PPARγ in normal and OA cartilage and to evaluate the effect of IL-1β, a prominent cytokine in OA, on PPARγ expression in cultured chondrocytes.

Immunohistochemical analysis revealed that the levels of PPARγ protein expression were significantly lower in OA cartilage when compared with normal cartilage. Using real-time RT-PCR, we demonstrated that PPARγ1 mRNA levels were ~10-fold higher than PPARγ2 mRNA levels; and that only PPARγ1 was differentially expressed, its levels in OA cartilage being 2.4-fold lower than in normal cartilage (P < 0.001). IL-1 treatment of OA chondrocytes downregulated PPARγ1 expression in a dose-dependent and time-dependent manner. This effect probably occurred at the transcriptional level, since IL-1 decreases both PPARγ1 mRNA expression and PPARγ1 promoter activity. TNFα, IL-17, and prostaglandin E2, which are involved in the pathogenesis of OA, also downregulated PPARγ1 expression. Specific inhibitors of the mitogen-activated protein kinase (MAPK) p38 (SB203580) and JNK (SP600125), but not Erk (PD98059), prevented IL-1-induced downregulation of PPARγ1 expression. Similarly, inhibitors of NF-κB signaling (PDTC, MG-132, and SN-50) abolished the suppressive effect of IL-1. In conclusion, our study has demonstrated for the first time that PPARγ1 is downregulated in OA cartilage. The proinflammatory cytokine IL-1 may be responsible for this downregulation via a mechanism involving activation of the MAPKs (p38 and JNK) and NF-κB signaling pathways. The IL-1-induced downregulation of PPARγ expression might be a new and additional important process by which IL-1 promotes articular inflammation and cartilage degradation.

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  • SB203580
  • PD98059
  • SP600125
  • Normal Cartilage
  • Articular Inflammation