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

Arthritis Research & Therapy

Christina Alexandra Manacu²  Johanne Martel-Pelletier¹  Marjolaine Roy-Beaudry²  Jean-Pierre Pelletier¹  Julio C Fernandes⁵  Fazool S Shipkolye²  Dragoslav R Mitrovic⁴  Florina Moldovan³ 

[1] Osteoarthritis Research Unit, Centre Hospitalier de l'Université de Montréal, Hopital Notre-Dame, Montreal, Quebec, Canada

[2] Research Center, Sainte-Justine Hospital, Montreal, Quebec, Canada

[3] Faculty of Dentistry, Université de Montréal, Quebec, Canada

[4] INSERM U-606, Hôpital Lariboisière, Paris, France

[5] Orthopaedics Research Laboratory, Department of Orthopaedics, Centre hospitalier Sacre-Coeur, Montreal, Quebec, Canada

关键词: signalling pathways;    osteoarthritis;    nitric oxide;    metalloproteases;    endothelin-1;   

Others  :  1101114
DOI  :  10.1186/ar1489

 received in 2004-04-20, accepted in 2004-12-01,  发布年份 2005

【 摘 要 】

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.

【 授权许可】

   
2005 Manacu et al., licensee BioMed Central Ltd.

【 图 表 】

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