15d‐PGJ2‐induced dedifferentiation and cyclooxygenase‐2 expression in articular chondrocytes via the ERK‐1/‐2 pathway

Abstract

Peroxisome proliferators-activated receptors (PPARs) are members of the ligand-activated nuclear receptor superfamily. PPARs bind to specific response elements as heterodimers with retinoid X receptor (RXR) and activate transcription in response to a variety of endogenous and exogenous ligands, whereas its physiological role is unclear. Therefore, we investigated the role of PPAR-gamma in COX-2 expression in articular chondrocytes with 15d-PGJ2, the natural receptor ligand for PPAR-gamma, Our experiments demonstrated that 15d-PGJ2 dose- and time-dependently induced dedifferentiation and COX-2 expression, but suppressed proliferation. The inductive effect seems to be dependent on PPAR-gamma activation, as the peroxisome proliferator response element (PPRE) luciferase activaty increased and PPAR antagonist, BADGE abolished it. Also, ectopic expression of PPAR-gamma was sufficient to cause dedifferentiation and COX-2 expression, wheareas dominant negative PPAR-gamma, S112A, suppressed 15d-PGJ2-induced dedifferentiation and COX-2 expression. We found that 15d-PGJ2 treatment stimulated activation of ERK-1/-2. Inhibition of ERK-1/-2 with PD98059 rescued 15d-PGJ2-induced dedifferentiation and blocked COX-2 expression. Our findings collectively suggest that PPAR-gamma-dependent regulation of dedifferentiation and COX-2 expression by 15d-PGJ2 via ERK-1/-2 in articular chondrocytes.