Treatment with a CO-releasing molecule (CORM-3) reduces joint inflammation and erosion in murine collagen-induced arthritis.
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 E(2) (PGE(2)) 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 kappaB ligand (RANKL) was examined by immunohistochemistry.


RESULTS
Therapeutic administration of CORM-3 suppressed clinical and histopathological manifestations of disease. The levels of PGE(2), interleukin (IL)1beta, IL2, IL6, IL10 and tumour necrosis factor (TNF)alpha 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.


CONCLUSIONS
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.
Department of Pharmacology, University of Valencia, Valencia, Spain.
M L
ML
Ferrándiz
N
N
Maicas
I
I
Garcia-Arnandis
M C
MC
Terencio
R
R
Motterlini
I
I
Devesa
L A B
LA
Joosten
W B
WB
van den Berg
M J
MJ
Alcaraz
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D051547:Heme Oxygenase-1 / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D009942:Organometallic Compounds / Q000627:therapeutic use*; D053245:RANK Ligand / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018836:Inflammation Mediators; D009942:Organometallic Compounds; D053245:RANK Ligand; C476530:tricarbonylchloro(glycinato)ruthenium(II); D018799:Intercellular Adhesion Molecule-1; D051547:Heme Oxygenase-1; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone