• Arthritis and rheumatism · Jul 2010

    Attenuation of pain and inflammation in adjuvant-induced arthritis by the proteasome inhibitor MG132.

    • Aisha S Ahmed, Jian Li, Mahmood Ahmed, Long Hua, Tatiana Yakovleva, Michael H Ossipov, Georgy Bakalkin, and André Stark.
    • Section of Orthopedics, Department of Molecular Medicine and Surgery, Karolinska University Hospital, Stockholm, Sweden. aisha.ahmed@ki.se
    • Arthritis Rheum. 2010 Jul 1;62(7):2160-9.

    ObjectiveIn rheumatoid arthritis (RA), pain and joint destruction are initiated and propagated by the production of proinflammatory mediators. Synthesis of these mediators is regulated by the transcription factor NF-kappaB, which is controlled by the ubiquitin proteasome system (UPS). The present study explored the effects of the proteasome inhibitor MG132 on inflammation, pain, joint destruction, and expression of sensory neuropeptides as markers of neuronal response in a rat model of arthritis.MethodsArthritis was induced in rats by injection of heat-killed Mycobacterium butyricum. Arthritis severity was scored, and nociception was evaluated by mechanical pressure applied to the hind paw. Joint destruction was assessed by radiologic and histologic analyses. NF-kappaB DNA-binding activity was analyzed by electromobility shift assay, and changes in the expression of the p50 NF-kappaB subunit and the proinflammatory neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) were detected by immunohistochemistry.ResultsArthritic rats treated with MG132 demonstrated a marked reduction in inflammation, pain, and joint destruction. The elevated DNA-binding activity of the NF-kappaB/p50 homodimer and p50, as well as the neuronal expression of SP and CGRP, observed in the ankle joints of arthritic rats were normalized after treatment with MG132.ConclusionIn arthritic rats, inhibition of proteasome reduced the severity of arthritis and reversed the pain behavior associated with joint inflammation. These effects may be mediated through the inhibition of NF-kappaB activation and may possibly involve the peripheral nervous system. New generations of nontoxic proteasome inhibitors may represent a novel pharmacotherapy for RA.

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