Bortezomib attenuates murine collagen-induced arthritis.
OBJECTIVE
Nuclear factor kappa B (NF-kappaB) is a major regulator of pivotal proinflammatory cytokines in the pathogenesis of rheumatoid arthritis (RA). Bortezomib inhibits NF-kappaB activation by blocking the degradation of the NF-kappaB inhibitor, I-kappaB. In this study, the efficacy of bortezomib on murine collagen-induced arthritis (CIA) was investigated.


METHODS
Thirty-five male DBA/1 mice were divided into five groups. All mice except controls were injected with type II collagen. Mice in the bortezomib-treated groups were injected intraperitoneally with 0.01, 0.1 and 1 mg/kg bortezomib twice a week for 2 weeks. Controls and mice in the untreated group were also injected intraperitoneally with phosphate-buffered saline in the same manner. Arthritis score and paw thickness were measured and histopathological assessment of joint sections was performed. The expression of proinflammatory cytokines and enzymes was evaluated by immunohistochemical staining. Joint destruction was confirmed using three-dimensional micro-computerised tomography (CT). Blood cells were counted and liver and kidney functions were monitored.


RESULTS
Bortezomib significantly attenuated the severity of arthritis and histopathological findings in CIA mice. The expression of tumour necrosis factor alpha, IL-1beta, IL-6, matrix metalloproteinase 3, cyclooxygenase 2 and inducible nitric oxide synthase decreased in bortezomib-treated mice compared with untreated mice. In addition, micro-CT confirmed that bortezomib reduced joint destruction. No adverse effects in blood cells, liver or kidneys were observed with bortezomib treatment.


CONCLUSIONS
These data suggest that bortezomib may play an anti-inflammatory role in the pathophysiology of RA and serve as a new therapeutic modality for RA.
Lee
S-W
SW
Department of Internal Medicine, Institute for Immunology and Immunological Disease, Yonsei University College of Medicine, Seoul, South Korea.
Kim
J-H
JH
Park
Y-B
YB
Lee
S-K
SK
D000818:Animals; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D001897:Boronic Acids / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D000069286:Bortezomib; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D011719:Pyrazines / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055114:X-Ray Microtomography
D018501:Antirheumatic Agents; D001897:Boronic Acids; D018836:Inflammation Mediators; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib