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PPARγ ligands inhibit catabolic and inflammatory responses in articular joint cells
Arthritis Res Ther volume 5, Article number: 35 (2003)
Overproduction of inflammatory and catabolic mediators in articular joint tissues is a hallmark of many rheumatic diseases such as osteoarthritis and rheumatoid arthritis. Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. In addition to their roles in lipid and glucid metabolism, PPARγ ligands have also been shown to modulate inflammatory responses in many cell types. We examined the expression of PPARγ and the effect of its ligands on inflammatory and catabolic responses in articular joint cells.
We showed that PPARγ is expressed and transcriptionally active in human chondrocytes and synoviocytes. Pretreatment of human chondrocytes with PPARγ ligands (15d-PGJ2 and BRL 49653) inhibited IL-1-induced nitric oxide and matrix metalloproteinase (MMP)-13 production. The induction of both inducible nitric oxide synthase and MMP-13 mRNA was inhibited in the presence of 15d-PGJ2. The inhibitory effect of PPARγ ligands was not restricted to IL-1, since tumor necrosis factor alpha and IL-17-induced nitric oxide and MMP-13 production were also inhibited by 15d-PGJ2. Similarly, pretreatment of synoviocytes with PPARγ ligands inhibited IL-1-induced MMP-1 at the protein and mRNA levels. The inhibitory effect of 15d-PGJ2 occurred at least in part through a PPARγ-dependent pathway, probably by interfering with the transcriptional activity of AP-1 and NF-κB. We also examined the effect of 15d-PGJ2 on cyclooxygenase-2 expression and prostaglandin E2 production, which are key players in the physiopathology of arthritis. We found that 15d-PGJ2 inhibits IL-1-induced cyclooxygenase-2 expression and prostaglandin E2 production in both cell types. Taken together, our data indicate that PPARγ activators may be useful in the development of new anti-arthritic agents.
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Fahmi, H., Pelletier, JP., Mineau, F. et al. PPARγ ligands inhibit catabolic and inflammatory responses in articular joint cells. Arthritis Res Ther 5 (Suppl 3), 35 (2003). https://doi.org/10.1186/ar836