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Endothelin-1 in osteoarthritic chondrocytes triggers nitric oxide production and upregulates collagenase production.
Arthritis Res Ther 2005; 7(2):R324-32AR

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.

Authors+Show Affiliations

Research Center, Sainte-Justine Hospital, Montreal, Quebec, Canada. crismanacu@yahoo.caNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15743480

Citation

Manacu, Christina Alexandra, et al. "Endothelin-1 in Osteoarthritic Chondrocytes Triggers Nitric Oxide Production and Upregulates Collagenase Production." Arthritis Research & Therapy, vol. 7, no. 2, 2005, pp. R324-32.
Manacu CA, Martel-Pelletier J, Roy-Beaudry M, et al. Endothelin-1 in osteoarthritic chondrocytes triggers nitric oxide production and upregulates collagenase production. Arthritis Res Ther. 2005;7(2):R324-32.
Manacu, C. A., Martel-Pelletier, J., Roy-Beaudry, M., Pelletier, J. P., Fernandes, J. C., Shipkolye, F. S., ... Moldovan, F. (2005). Endothelin-1 in osteoarthritic chondrocytes triggers nitric oxide production and upregulates collagenase production. Arthritis Research & Therapy, 7(2), pp. R324-32.
Manacu CA, et al. Endothelin-1 in Osteoarthritic Chondrocytes Triggers Nitric Oxide Production and Upregulates Collagenase Production. Arthritis Res Ther. 2005;7(2):R324-32. PubMed PMID: 15743480.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Endothelin-1 in osteoarthritic chondrocytes triggers nitric oxide production and upregulates collagenase production. AU - Manacu,Christina Alexandra, AU - Martel-Pelletier,Johanne, AU - Roy-Beaudry,Marjolaine, AU - Pelletier,Jean-Pierre, AU - Fernandes,Julio C, AU - Shipkolye,Fazool S, AU - Mitrovic,Dragoslav R, AU - Moldovan,Florina, Y1 - 2005/01/17/ PY - 2004/04/20/received PY - 2004/11/10/revised PY - 2004/12/01/accepted PY - 2005/3/4/pubmed PY - 2005/12/16/medline PY - 2005/3/4/entrez SP - R324 EP - 32 JF - Arthritis research & therapy JO - Arthritis Res. Ther. VL - 7 IS - 2 N2 - 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. SN - 1478-6362 UR - https://www.unboundmedicine.com/medline/citation/15743480/Endothelin_1_in_osteoarthritic_chondrocytes_triggers_nitric_oxide_production_and_upregulates_collagenase_production_ L2 - https://arthritis-research.biomedcentral.com/articles/10.1186/ar1489 DB - PRIME DP - Unbound Medicine ER -