The CO-releasing molecule CORM-3 protects against articular degradation in the K/BxN serum transfer arthritis model.
Carbon monoxide-releasing molecules can counteract inflammatory responses. The aim of this study was to investigate whether tricarbonylchloro(glycinate)ruthenium (II) (CORM-3) is able to control the effector phase of experimental arthritis. Arthritis was induced in C57Black-6 mice by an intraperitoneal injection of serum from arthritic K/BxN mice. CORM-3 was administered intraperitoneally at 10 mg/kg/day (5 mg/kg twice a day) from days 0 to 10 and animals were sacrificed on day 11. Serum levels of osteocalcin and prostanoids were measured by enzyme-linked immunosorbent assay and radioimmunoassay. Gene expression was determined by real-time PCR. Histological analysis was performed and protein expression was examined by immunohistochemistry. Treatment with CORM-3 reduced the macroscopic score in hind paws, the migration of inflammatory cells and erosion of cartilage and bone. CORM-3 increased the levels of osteocalcin in the serum and reduced PGD2 levels, whereas PGE2 and 6-ketoPGF1alpha were not affected. In synovial tissues, we also observed a significant reduction in gene expression of interleukin-1beta, receptor activator of nuclear factor kappaB ligand (RANKL), matrix metalloproteinase (MMP)-9 and MMP-13. CORM-3 induced HO-1 expression in joint tissues but inhibited high mobility group box 1 (HMGB1), hematopoietic-prostaglandin D2 synthase (H-PGDS) and lipocalin-type prostaglandin D2 synthase (L-PGDS), as well as RANKL and intercellular adhesion molecule-1. COX-2 expression was not affected by CORM-3 treatment. We have shown that CORM-3 decreases the inflammatory response and protects against the degradation of cartilage and bone in the arthritic mice. Pharmacological CO delivery represents a novel strategy to regulate the effector phase of arthritis.
Maicas
Nuria
N
Department of Pharmacology, University of Valencia, Av. Vicent Andres Estelles s/n, 46100 Burjasot, Valencia, Spain.
Ferrándiz
Maria Luisa
ML
Devesa
Isabel
I
Motterlini
Roberto
R
Koenders
Marije I
MI
van den Berg
Wim B
WB
Alcaraz
Maria José
MJ
D000818:Animals; D001169:Arthritis, Experimental / Q000097:blood* / Q000473:pathology / Q000517:prevention & control*; D002248:Carbon Monoxide / Q000378:metabolism*; D002358:Cartilage, Articular / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009942:Organometallic Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D012428:Ruthenium / Q000627:therapeutic use; D044967:Serum / Q000276:immunology
D009942:Organometallic Compounds; C476530:tricarbonylchloro(glycinato)ruthenium(II); D002248:Carbon Monoxide; D012428:Ruthenium