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.
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.
Yoon
Eun Kyung
EK
Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju, Korea.
Lee
Won Kil
WK
Lee
Ji Hye
JH
Yu
Seon Mi
SM
Hwang
Sang Gu
SG
Kim
Song Ja
SJ
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*
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