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Peroxynitrite-modified collagen-II induces p38/ERK and NF-kappa B-dependent synthesis of prostaglandin E-2 and nitric oxide in chondrogenically differentiated mesenchyrnal progenitor cells

Whiteman, M., Spencer, J.P.E., Zhu, Y.Z., Armstrong, J.S. and Schantz, J.T. (2006) Peroxynitrite-modified collagen-II induces p38/ERK and NF-kappa B-dependent synthesis of prostaglandin E-2 and nitric oxide in chondrogenically differentiated mesenchyrnal progenitor cells. Osteoarthritis and Cartilage, 14 (5). pp. 460-470. ISSN 1063-4584

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To link to this article DOI: 10.1016/j.joca.2005.11.002

Abstract/Summary

Objective: Peroxynitrite (ONOO-) is formed in the inflamed and degenerating human joint. Peroxynitrite-modified collagen-II (PMC-II) was recently discovered in the serum of patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Therefore we investigated the cellular effects of PMC-II on human mesenchymal progenitor cells (MPCs) as a model of cartilage and cartilage repair cells in the inflamed and degenerating joint. Design: MPCs were isolated from the trabecular bone of patients undergoing reconstructive surgery and were differentiated into a chondrogenic lineage. Cells were exposed to PMC-II and levels of the proinflammatory mediators nitric oxide (NO) and prostaglandin E-2 (PGE(2)) measured. Levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), phosphorylated mitogen activated protein kinases (MAPKs) and nuclear factor kappa B (NF-kappa B) activation were measured by enzyme linked immunosorbent assay (ELISA) together with specific MAPK and NF-kappa B inhibitors. Results: PMC-II induced NO and PGE(2) synthesis through upregulation of iNOS and COX-2 proteins. PMC-II also lead to the phosphorylation of MAPKs, extracellularly regulated kinase 1/2 (ERK1/2) and p38 [but not c-Jun NH2-terminal kinase (JNK1/2)] and the activation of proinflammatory transcription factor NF-kappa B. Inhibitors of p38, ERK1/2 and NF-kappa B prevented PMC-II induced NO and PGE(2) synthesis, NOS and COX-2 protein expression and NF-kappa B activation. Conclusion: iNOS, COX-2, NF-KB and MAPK are known to be activated in the joints of patients with OA and RA. PMC-II induced iNOS and COX-2 synthesis through p38, ERK1/2 and NF-KB dependent pathways suggesting a previously unidentified pathway for the synthesis of the proinflammatory mediators, NO and PGE(2), further suggesting that inhibitors of these pathways may be therapeutic in the inflamed and degenerating human joint. (c) 2005 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Item Type:Article
Refereed:Yes
Divisions:Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR)
Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > Department of Food and Nutritional Sciences
Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > Department of Food and Nutritional Sciences > Human Nutrition Research Group
ID Code:12856
Uncontrolled Keywords:peroxynitrite, nitric oxide, chondrocyte, osteoarthritis, rheumatoid arthritis , ACTIVATED PROTEIN-KINASE, RHEUMATOID-ARTHRITIS, IN-VIVO, HYPOCHLOROUS ACID, REACTIVE OXYGEN, EXPERIMENTAL OSTEOARTHRITIS, OXIDATIVE DAMAGE, ARTICULAR CHONDROCYTES, ANTIINFLAMMATORY AGENT, SELECTIVE-INHIBITION
Additional Information:Whiteman, M Spencer, J P E Zhu, Y Z Armstrong, J S Schantz, J-T Research Support, Non-U.S. Gov't England Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society Osteoarthritis Cartilage. 2006 May;14(5):460-70. Epub 2006 Jan 19.

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