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Rheumatology Advance Access published online on July 11, 2008
Rheumatology, doi:10.1093/rheumatology/ken264
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The CO-releasing molecule CORM-2 is a novel regulator of the inflammatory process in osteoarthritic chondrocytes

M. I. Guillén1,2, J. Megías1, V. Clérigues1, F. Gomar3 and M. J. Alcaraz1

1Department of Pharmacology, University of Valencia, 2Department of Chemistry, Biochemistry and Molecular Biology, Cardenal Herrera-CEU University and 3Department of Surgery, Faculty of Medicine, University of Valencia, Valencia, Spain

Correspondence to: M. J. Alcaraz, Department of Pharmacology, University of Valencia, Av. Vicent Andrés Estellés s/n, 46100 Burjasot, Valencia, Spain. E-mail: maria.j.alcaraz{at}uv.es


  Abstract

Objectives. Previous work has shown that the CO-releasing molecule CORM-2 protects against cartilage degradation. The aim of this study was to examine whether CORM-2 can control the production of inflammatory mediators in osteoarthritic chondrocytes and determine the mechanisms involved.

Methods. Primary cultures of chondrocytes from OA patients were stimulated with IL-1β. The production of reactive oxygen species, nitrite, PGE2, TNF-{alpha} and IL-1 receptor antagonist (IL-1Ra) were measured in the presence or absence of CORM-2. The expression of nitric oxide synthase-2 (NOS-2), cyclo-oxygenase-2 (COX-2) and microsomal PG E synthase-1 (mPGES-1) was followed by western blot and real-time PCR. Activation of nuclear factor-{kappa}B (NF-{kappa}B) and hypoxia inducible factor-1{alpha} (HIF-1{alpha}), and phosphorylation of NF-{kappa}B inhibitory protein {alpha} (I{kappa}B{alpha}) were determined by ELISA.

Results. CORM-2 decreased the production of oxidative stress, nitrite and PGE2. In addition, CORM-2 inhibited IL-1β-induced TNF-{alpha} but enhanced IL-1Ra production. Treatment of chondrocytes with CORM-2 strongly down-regulated NOS-2 and mPGES-1 protein expression, whereas COX-2 was reduced to a lesser extent. These changes were accompanied by a significant decrease in mRNA expression for NOS-2 and mPGES-1. CORM-2 showed a concentration-dependent inhibition of DNA-binding activity for p65 NF-{kappa}B and HIF-1{alpha}. I{kappa}B{alpha} phosphorylation was also reduced by CORM-2 treatment.

Conclusions. These data have opened new mechanisms of action for CORM-2, raising the prospect that CO-releasing molecules are an interesting strategy for the development of new treatments in articular conditions.

KEY WORDS: Osteoarthritis, Chondrocyte, CO-releasing molecules, Cytokines, Nitric oxide, Oxidative stress, Nuclear factor-{kappa}B, Hypoxia inducible factor-1{alpha}

Submitted 27 March 2008; revised version accepted 18 June 2008.
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