ERK-1/-2 and p38 Kinase Oppositely Regulate 15-deoxy-Δ(12,14)-prostaglandinJ(2)-Induced PPAR-γ Activation That Mediates Dedifferentiation But Not Cyclooxygenase-2 Expression in Articular Chondrocytes

Peroxisome proliferator-activated receptor gamma (PPAR-γ) is a ligand-activated transcription factor and plays an important role in growth, differentiation, and inflammation in different tissues. In this study, we investigated the effects of 15d-PGJ(2), a high-affinity ligand of PPAR-γ, on dedifferentiation and on inflammatory responses such as COX-2 expression and PGE(2) production in rabbit articular chondrocytes with a focus on ERK-1/-2, p38 kinase, and PPAR-γ activation. We report here that 15d-PGJ(2) induced dedifferentiation and/or COX-2 expression and subsequent PGE(2) production. 15d-PGJ(2) treatment stimulated activation of ERK-1/-2, p38 kinase, and PPAR-γ. Inhibition of ERK-1/-2 with PD98059 recovered 15d-PGJ(2)-induced dedifferentiation and enhanced PPAR-γ activation, whereas inhibition of p38 kinase with SB203580 potentiated dedifferentiation and partially blocked PPAR-γ activation. Inhibition of ERK-1/-2 and p38 kinase abolished 15d-PGJ(2)-induced COX-2 expression and subsequent PGE(2) production. Our findings collectively suggest that ERK-1/-2 and p38 kinase oppositely regulate 15d-PGJ(2)-induced dedifferentiation through a PPAR-γ-dependent mechanism, whereas COX-2 expression and PGE(2) production is regulated by ERK-1/-2 through a PPAR-γ-independent mechanism but not p38 kinase in articular chondrocytes. Additionally, these data suggest that targeted modulation of the PPAR-γ and mitogen-activated protein kinase pathway may offer a novel approach for therapeutic inhibition of joint tissue degradation.