Reduction in the evolution of murine type II collagen-induced arthritis by treatment with rosiglitazone, a ligand of the peroxisome proliferator-activated receptor gamma.
OBJECTIVE
The peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid, and thyroid hormone receptors. The thiazolidinedione rosiglitazone is a PPARgamma ligand that modulates the transcription of target genes. The aim of this study was to investigate the effects of rosiglitazone on the inflammatory response in mice with collagen-induced arthritis (CIA).


METHODS
CIA was induced in DBA/1J mice by an intradermal injection of 100 microl of an emulsion of bovine type II collagen (CII; 100 microg) in Freund's complete adjuvant (CFA) at the base of the tail. On day 21, a second injection of CII in CFA was administered. Rosiglitazone (10 mg/kg/day) or vehicle (10% DMSO) was administered beginning on day 25 (arthritis onset) until day 35. Clinical, radiographic, histopathologic, and laboratory assessments were performed.


RESULTS
Mice immunized with CII in CFA developed erosive arthritis of the hind paws. Macroscopic evidence of CIA first appeared as periarticular erythema and edema of the hind paws. The incidence of CIA was 100% by day 27 in the CII-challenged mice, and the severity progressed over the 35-day study period. Radiographic evaluation revealed focal resorption of bone. Histopathologic features of CIA included erosion of cartilage at the joint margins. Rosiglitazone treatment ameliorated the clinical signs on days 26-35 and improved the histologic findings in the joint and paw. The degree of oxidative and nitrosative damage was significantly reduced in rosiglitazone-treated mice, as indicated by elevation of malondialdehyde levels, formation of nitrotyrosine, and activation of poly(ADP-ribose) polymerase. Plasma levels of the proinflammatory cytokines tumor necrosis factor, interleukin-1beta, and interleukin-6 were also significantly reduced by rosiglitazone treatment.


CONCLUSIONS
These data demonstrate that rosiglitazone exerts an antiinflammatory effect on chronic inflammation and is able to ameliorate the tissue damage associated with CIA.
Cuzzocrea
Salvatore
S
University of Messina, Messina, Italy. salvator@unime.it
Mazzon
Emanuela
E
Dugo
Laura
L
Patel
Nimesh S A
NS
Serraino
Ivana
I
Di Paola
Rosanna
R
Genovese
Tiziana
T
Britti
Domenico
D
De Maio
Massimo
M
Caputi
Achille P
AP
Thiemermann
Christoph
C
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D024043:Collagen Type II; D051546:Cyclooxygenase 2; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007596:Joints / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D008811:Mice, Inbred DBA; D009504:Neutrophils / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D014665:Vasodilator Agents / Q000494:pharmacology*
D024043:Collagen Type II; D007375:Interleukin-1; D015850:Interleukin-6; D007527:Isoenzymes; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D000077154:Rosiglitazone; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D011065:Poly(ADP-ribose) Polymerases