Objective: CO-releasing molecules (CO-RMs) are a novel class of anti-inflammatory agents. We have examined the possible therapeutic effects of CORM-3 in collagen-induced arthritis (CIA).
Methods: Arthritis was induced in DBA-1/J mice by type II collagen. Animals were treated with CORM-3 (5 and 10 mg/kg/day, intraperitoneally) or the inactive compound iCORM-3 (10 mg/kg/day, intraperitoneally) unable to release CO, from days 22 to 31. Production of anti-type II collagen antibodies, cytokines and cartilage olimeric matrix protein (COMP) was evaluated by enzyme-linked immunosorbent assay, and prostaglandin E2 (PGE2) by radioimmunoassay. Localisation of cyclooxygenase-2 (COX-2), haem oxygenase-1 (HO-1), intercellular adhesion molecule-1 (ICAM-1) and receptor activator of nuclear factor κB ligand (RANKL) was examined by immunohistochemistry.
Results: Therapeutic administration of CORM-3 suppressed clinical and histopathological manifestations of disease. The levels of PGE2, interleukin (IL)1β, IL2, IL6, IL10 and tumour necrosis factor (TNF)α in joint tissues were inhibited by CORM-3. By contrast, CORM-3 augmented IL4. Anti-type II collagen antibodies and COMP levels in serum were reduced by CORM-3. Treatment with CORM-3 decreased cellular infiltration, joint inflammation and destruction, as well as the expression of COX-2, ICAM-1 and RANKL, whereas HO-1 increased. These beneficial effects were due to CO release, as iCORM-3 was ineffective.
Conclusion: This study reveals the antiarthritic properties of CORM-3 in the CIA model and supports the notion that CO-RMs could be developed as a novel strategy for the treatment of inflammatory and arthritic conditions.
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Funding: This work was funded by public grants from Spanish Ministerio de Educación y Ciencia-FEDER (SAF2004-03835 and N Maicas fellowship) and Generalitat Valenciana (ACOMP2007-066, GV06/357 and I Garcia-Arnandis fellowship).
Competing interests: RM has financial interests in Hemocorm.
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