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Interleukin-1β induced activation of nuclear factor-κb can be inhibited by novel pharmacological agents in osteoarthritis

Lauder, S. N., Carty, S. M., Carpenter, C. E., Hill, R. J., Talamas, F., Bondeson, Jan, Brennan, P. and Williams, A. S. 2007. Interleukin-1β induced activation of nuclear factor-κb can be inhibited by novel pharmacological agents in osteoarthritis. Rheumatology 46 (5) , pp. 752-758. 10.1093/rheumatology/kel419

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Objectives. To investigate the importance of activation of the transcription factor, nuclear factor-κB (NF-κB) by interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α) in the pathogenesis of osteoarthritis (OA) and assess its suitability as a target for therapy by determining its role in the induction of the cytokine IL-6 and the degenerative enzymes, matrix metalloproteinase (MMP)-1 and MMP-3 in vitro. Methods. Three distinct cellular models, derived from primary OA tissue, were employed, namely, fibroblast-like synoviocytes (OA-SF); co-cultures containing phenotypic macrophage-like and fibroblast-like cells (OA-COCUL); and primary OA synovial tissue explants (OA-EXP). These were treated with specific inhibitors of IL-1β, TNF-α and NF-κB to assess their differential role in the production of pathologically relevant mediators, specifically IL-6, MMP-1, MMP-3 and the tissue inhibitor of metalloproteinases-1 (TIMP-1), which were quantified by enzyme-linked immunosorbent assay. Results. Inhibition of NF-κB by a novel agent, RO100 at a dose of 0.1 μM, exerted significant (P < 0.05) repression of IL-6, MMP-1 and MMP-3 production in OA-SF. Notably, neither TIMP-1 production nor cell viability was significantly affected at the dose tested. These data were reproduced in OA-EXP, which might be considered as having greater physiological relevance. Interestingly, comparable efficacy was noted using IL-1β and TNF-α neutralizing antibodies in OA-COCUL. Conclusions. We have demonstrated that a novel pharmacological inhibitor of NF-κB, RO100 inhibits pathological mediators of OA progression with equivalent efficacy as established IL-1β and TNF-α neutralizing strategies. Our findings highlight a potential for developing NF-κB targeted therapeutics for positively regulating disease activity and improving clinical outcome in OA.

Item Type: Article
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
ISSN: 14620324
Last Modified: 30 Jun 2017 03:25

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