Prostaglandin J2 causes dedifferentiation via PPAR‐gamma‐dependent pathway, but not COX‐2 expression in articular chondrocyte.

Abstract

The peroxisome proliferator-activated receptors(PPARs) represent a family of nuclear receprtor ligand activated transcription factors that have been implicated in maintenance of lipid and glucose homeostasis, control of cell growth and differentiation, and regulation of inflammation. PPARs bind to specific response elements as heterodimers with retinoid X receptor (RXR) and activate transcription in response to a variety of endogenouse and exogenouse ligands, whereas its physiological role is unclear. Therefore we investigated the role of PPAR-gamma in dedifferantiation and COX-2 expression in articular chondrocyte with 15d-PGJ2, the natural receptor ligand for PPAR-gamma. Our experiments demonstrated that 15d-PGJ2 dose- and time-dependently induced dedifferantiation and COX-2 expression. The inductive effect on dedifferentiation of chondrocyte seems to be dependent on PPAR activation, as the peroxisome proliferator response element(PPRE) luciferase activity increased and PPAR antagonist, BADGE abolished it. Also, ectopic expression of PPAR-gamma was sufficient to cause dedifferentiation, whereas dominant negative PPAR-gamma, S112A, suppressed 15d-PGJ2-induced dedifferentiation. In the other hands, COX-2 expression was not affected by treatment of PPAR-gamma antagonist(BADGE) as well as transfection of PPAR-gamma dominant negative mutant(S112A). These results indicate that COX-2 regulation by 15d-PGJ2 is independent on PPAR-gamma signaling pathway. Additionally, these data suggest that targeted modulation of the PPAR-gamma pathway may offer a novel approach for therapeutic inhibition of joint tissue.