Rheumatology Advance Access originally published online on July 11, 2008
Rheumatology 2008 47(9):1323-1328; doi:10.1093/rheumatology/ken264
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The CO-releasing molecule CORM-2 is a novel regulator of the inflammatory process in osteoarthritic chondrocytes
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
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Abstract |
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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-
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-
B (NF-B) and hypoxia inducible factor-1 (HIF-1), and phosphorylation of NF-B inhibitory protein (IB) 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- 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-B and HIF-1. IB 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-B, Hypoxia inducible factor-1
Submitted 27 March 2008;
revised version accepted 18 June 2008.
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