Effects of agonists of peroxisome proliferator-activated receptor γ on proteoglycan degradation and matrix metalloproteinase production in rat cartilage in vitro

Objective: To examine the effects of agonists of peroxisome proliferator-activated receptor (PPAR) gamma on proteoglycan degradation induced by interleukin (IL)-1beta or tumor necrosis factor (TNF)alpha in cartilage in vitro. Design: Proteoglycan degradation was measured as release of radioactivity from rat cartilage explants previously labeled with (SO42-)-S-35. Western blots were used to examine tissue levels of aggrecan neoepitopes NITEGE and VDIPEN, generated by aggrecanases and matrix metalloproteinases (MMP), respectively. Production of MMP-2, -3 and -9 by cultured rat chondrocytes was measured by zymography and by fluorimetric assay. Results: IL-1beta-induced proteoglycan degradation was likely due to aggrecanase, since it was associated with a strong increase of NITEGE signal. MMP-dependent VDIPEN signal increased only after further incubation with pro-MMP activator APMA. PPAR agonists 15d-PGJ(2) and G1262570 (10 muM) inhibited IL-1beta- and TNFalpha-induced proteoglycan degradation measured both before and after addition of APMA. The agonists also inhibited cytokine-induced MMP production by isolated chondrocytes. Conclusion: This study shows that PPAR gamma agonists inhibit cytokine-induced proteoglycan degradation mediated by both aggrecanase and MMP. This effect is associated with inhibition of production of MMP-3 and -9. These results support the interest for PPAR gamma agonists as candidate inhibitors of pathological cartilage degradation. (C) 2002 OsteoArthritis Research Society International. Published by Elsevier Science Ltd. All rights reserved.