title: ERK-1/-2 and p38 kinase oppositely regulate 15-deoxy-delta(12,14)-prostaglandinJ(2)-Induced PPAR-gamma activation that mediates dedifferentiation but not cyclooxygenase-2 expression in articular chondrocytes.
abstract: Peroxisome proliferator-activated receptor gamma (PPAR-gamma) 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-gamma, 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-gamma 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-gamma. Inhibition of ERK-1/-2 with PD98059 recovered 15d-PGJ(2)-induced dedifferentiation and enhanced PPAR-gamma activation, whereas inhibition of p38 kinase with SB203580 potentiated dedifferentiation and partially blocked PPAR-gamma 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-gamma-dependent mechanism, whereas COX-2 expression and PGE(2) production is regulated by ERK-1/-2 through a PPAR-gamma-independent mechanism but not p38 kinase in articular chondrocytes. Additionally, these data suggest that targeted modulation of the PPAR-gamma and mitogen-activated protein kinase pathway may offer a novel approach for therapeutic inhibition of joint tissue degradation.
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju, Korea.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Yoon
authors.forename: Won Kil
authors.initials: WK
authors.lastname: Lee
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Lee
authors.forename: Seon Mi
authors.initials: SM
authors.lastname: Yu
authors.forename: Sang Gu
authors.initials: SG
authors.lastname: Hwang
authors.forename: Song Ja
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology*; D002454:Cell Differentiation / Q000187:drug effects; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000032:analysis*; D015232:Dinoprostone / Q000096:biosynthesis; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D047495:PPAR gamma / Q000502:physiology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011817:Rabbits; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D047495:PPAR gamma; D051546:Cyclooxygenase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone; D015230:Prostaglandin D2