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Endothelin-1 in osteoarthritic chondrocytes triggers nitric oxide production and upregulates collagenase production.

Abstract : The mechanism of endothelin-1 (ET-1)-induced nitric oxide (NO) production, MMP-1 production and MMP-13 production was investigated in human osteoarthritis chondrocytes. The cells were isolated from human articular cartilage obtained at surgery and were cultured in the absence or presence of ET-1 with or without inhibitors of protein kinase or LY83583 (an inhibitor of soluble guanylate cyclase and of cGMP). MMP-1, MMP-13 and NO levels were then measured by ELISA and Griess reaction, respectively. Additionally, inducible nitric oxide synthase (iNOS) and phosphorylated forms of p38 mitogen-activated protein kinase, p44/42, stress-activated protein kinase/Jun-N-terminal kinase and serine-threonine Akt kinase were determined by western blot. Results show that ET-1 greatly increased MMP-1 and MMP-13 production, iNOS expression and NO release. LY83583 decreased the production of both metalloproteases below basal levels, whereas the inhibitor of p38 kinase, SB202190, suppressed ET-1-stimulated production only. Similarly, the ET-1-induced NO production was partially suppressed by the p38 kinase inhibitor and was completely suppressed by the protein kinase A kinase inhibitor KT5720 and by LY83583, suggesting the involvement of these enzymes in relevant ET-1 signalling pathways. In human osteoarthritis chondrocytes, ET-1 controls the production of MMP-1 and MMP-13. ET-1 also induces NO release via iNOS induction. ET-1 and NO should thus become important target molecules for future therapies aimed at stopping cartilage destruction.
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Submitted on : Thursday, September 14, 2006 - 1:51:10 PM
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Christina Alexandra Manacu, Johanne Martel-Pelletier, Marjolaine Roy-Beaudry, Jean-Pierre Pelletier, Julio C. Fernandes, et al.. Endothelin-1 in osteoarthritic chondrocytes triggers nitric oxide production and upregulates collagenase production.. Arthritis Research and Therapy, BioMed Central, 2005, 7, pp.R324-32. ⟨10.1186/ar1489⟩. ⟨inserm-00094003⟩



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