15-Deoxy-Δ(12,14)-ProstaglandinJ2 Regulates Dedifferentiation through Peroxisome Proliferator-Activated Receptor-γ-Dependent Pathway but Not COX-2 Expression in Articular Chondrocytes

Peroxisome proliferator-activated receptors-γ (PPAR-γ) is critical for phenotype determination at early differentiation stages of mesenchymal cells, whereas its physiological role is unclear. Therefore, we investigated the role of 15-deoxy-Δ(12,14)-prostaglandinJ2 (15d-PGJ2), the natural receptor ligand for PPAR-γ, on dedifferentiation and inflammatory responses, such as COX-2 expression and PGE(2) production, in articular chondrocytes. Our data indicate that the 15d-PGJ2 caused a loss of differentiated chondrocyte phenotype as demonstrated by inhibition of type II collagen and proteoglycan synthesis. 15d-PGJ2 also induced COX-2 expression and PGE(2) production. The 15d-PGJ2-induced dedifferentiation effect seems to be dependent on PPAR-γ activation, as the PPRE luciferase activity increased and PPAR-γ antagonist, BADGE, abolished type II collagen expression. However, BADGE did not block 15d-PGJ2-induced COX-2 expression. Collectively, our findings suggest that PPAR-γ-dependent and -independent mechanisms of 15d-PGJ2-induced dedifferentiation and inflammatory responses in articular chondrocytes, respectively. Additionally, these data suggest that targeted modulation of the PPAR-γ pathway may offer a novel approach for therapeutic inhibition of joint tissue degradation.