Peroxisome proliferator-activated receptor gamma1 expression is diminished in human osteoarthritic cartilage and is downregulated by interleukin-1beta in articular chondrocytes.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor involved in the regulation of many cellular processes. We and others have previously shown that PPARgamma activators display anti-inflammatory and chondroprotective properties in vitro and improve the clinical course and histopathological features in an experimental animal model of osteoarthritis (OA). However, the expression and regulation of PPARgamma expression in cartilage are poorly defined. This study was undertaken to investigate the quantitative expression and distribution of PPARgamma in normal and OA cartilage and to evaluate the effect of IL-1beta, a prominent cytokine in OA, on PPARgamma expression in cultured chondrocytes. Immunohistochemical analysis revealed that the levels of PPARgamma protein expression were significantly lower in OA cartilage than in normal cartilage. Using real-time RT-PCR, we demonstrated that PPARgamma1 mRNA levels were about 10-fold higher than PPARgamma2 mRNA levels, and that only PPARgamma1 was differentially expressed: its levels in OA cartilage was 2.4-fold lower than in normal cartilage (p < 0.001). IL-1 treatment of OA chondrocytes downregulated PPARgamma1 expression in a dose- and time-dependent manner. This effect probably occurred at the transcriptional level, because IL-1 decreases both PPARgamma1 mRNA expression and PPARgamma1 promoter activity. TNF-alpha, IL-17, and prostaglandin E2 (PGE2), which are involved in the pathogenesis of OA, also downregulated PPARgamma1 expression. Specific inhibitors of the mitogen-activated protein kinases (MAPKs) p38 (SB203580) and c-Jun N-terminal kinase (SP600125), but not of extracellular signal-regulated kinase (PD98059), prevented IL-1-induced downregulation of PPARgamma1 expression. Similarly, inhibitors of NF-kappaB signaling (pyrrolidine dithiocarbamate, MG-132, and SN-50) abolished the suppressive effect of IL-1. Thus, our study demonstrated that PPARgamma1 is downregulated in OA cartilage. The pro-inflammatory cytokine IL-1 may be responsible for this downregulation via a mechanism involving activation of the MAPKs (p38 and JNK) and NF-kappaB signaling pathways. The IL-1-induced downregulation of PPARgamma expression might be a new and additional important process by which IL-1 promotes articular inflammation and cartilage degradation.
Afif
Hassan
H
Osteoarthritis Research Unit, Centre Hospitalier de l'Université de Montréal, Montreal, 1560 Sherbrooke East, Pavillon J,A DeSève, Y-2628, Montreal, QC, H2L 4M1, Canada. hassanafif@sympatico.ca
Benderdour
Mohamed
M
Mfuna-Endam
Leandra
L
Martel-Pelletier
Johanne
J
Pelletier
Jean-Pierre
JP
Duval
Nicholas
N
Fahmi
Hassan
H
D015153:Blotting, Western; D002356:Cartilage / Q000378:metabolism*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000187:drug effects; D010003:Osteoarthritis / Q000378:metabolism*; D047495:PPAR gamma / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects
D004791:Enzyme Inhibitors; D020381:Interleukin-17; D053583:Interleukin-1beta; D016328:NF-kappa B; D047495:PPAR gamma; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D015232:Dinoprostone