Treatment with a CO-releasing molecule (CORM-3) reduces joint inflammation and erosion in murine collagen-induced arthritis
- M L Ferrándiz1,
- N Maicas1,
- I Garcia-Arnandis1,
- M C Terencio1,
- R Motterlini2,
- I Devesa3,
- L A B Joosten3,
- W B van den Berg3,
- M J Alcaraz1
- 1Department of Pharmacology, University of Valencia, Valencia, Spain
- 2Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex, UK
- 3Rheumatology Research & Advanced Therapeutics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
- Professor M J Alcaraz, Department of Pharmacology, University of Valencia, Avda. Vicent Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain;
- Accepted 2 December 2007
- Published Online First 6 December 2007
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.
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.