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

• Published in: Rheumatology (Oxford, England) Vol. 47; no. 9; pp. 1323 - 1328
• Main Authors: Guillén, M. I., Megías, J., Clérigues, V., Gomar, F., Alcaraz, M. J.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.09.2008; Oxford Publishing Limited (England)
• Subjects: Aged; Aged, 80 and over; Biological and medical sciences; Cells, Cultured; Chondrocyte; Chondrocytes - drug effects; Chondrocytes - pathology; CO-releasing molecules; Cyclooxygenase 2 - metabolism; Cytokines; Dinoprostone - biosynthesis; Diseases of the osteoarticular system; Dose-Response Relationship, Drug; Female; Humans; Hypoxia inducible factor-1α; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Interleukin 1 Receptor Antagonist Protein - biosynthesis; Interleukin-1beta - physiology; Intramolecular Oxidoreductases - metabolism; Male; Medical sciences; Miscellaneous. Osteoarticular involvement in other diseases; NF-kappa B - metabolism; Nitric oxide; Nitric Oxide - biosynthesis; Nitric Oxide Synthase Type II - metabolism; Nuclear factor-κB; Organometallic Compounds - pharmacology; Osteoarthritis; Osteoarthritis - metabolism; Osteoarthritis - pathology; Oxidative stress; Prostaglandin-E Synthases; Reactive Oxygen Species - metabolism; Tumor Necrosis Factor-alpha - biosynthesis; Oxidative stress; Chondrocyte; Cytokines; Hypoxia inducible factor-1α; Nitric oxide; Nuclear factor-κB; Osteoarthritis; CO-releasing molecules; Oxygen; Diseases of the osteoarticular system; Cytokine; Rheumatology; Arthropathy; Hypoxia; Degenerative disease; Transcription factor NFκB
• ISSN: 1462-0324; 1462-0332
• DOI: 10.1093/rheumatology/ken264

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-α 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-κB (NF-κB) and hypoxia inducible factor-1α (HIF-1α), and phosphorylation of NF-κB inhibitory protein α (IκBα) 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-α 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-κB and HIF-1α. IκBα 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.