Objectives: Nuclear factor-kappa B (NF-κB) is a major regulator of pivotal proinflammatory cytokines in rheumatoid arthritis (RA) pathogenesis. Bortezomib inhibits NF-κB activation by blocking the degradation of the NF-κB inhibitor, I-κB. In this study, we investigated the efficacy of bortezomib on murine collagen-induced arthritis (CIA).
Methods: Thirty-five male DBA/1 mice were divided into 5 groups. All mice except controls were injected with type II collagen. Mice in the bortezomib-treated groups were intraperitoneally (IP) injected with 0.01, 0.1, and 1 mg/kg of bortezomib twice a week for 2 weeks. Controls and mice in the untreated group were also IP injected with PBS in the same manner. Arthritis score and paw thickness were measured and histopathologic assessment of joint sections was performed. Expression of proinflammatory cytokines and enzymes was evaluated by immunohistochemical staining. Joint destruction was confirmed using 3-dimensional micro-computerized tomography (CT). We counted blood cells and monitored liver and kidney functions.
Results Bortezomib significantly attenuated arthritis severity and histopathologic findings in CIA mice. Tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, matrix metalloproteinase (MMP)-3, cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS) expression decreased in bortezomib-treated mice compared to untreated mice. In addition, micro-CT confirmed that bortezomib reduced joint destruction. No adverse effects in blood cells, liver, and 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.