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

• Published in: Rheumatology (Oxford, England) England), 2007-05, Vol.46 (5), p.752-758
• Main Authors: Lauder, S. N., Carty, S. M., Carpenter, C. E., Hill, R. J., Talamas, F., Bondeson, J., Brennan, P., Williams, A. S.
• Format: Article
• Language: English
• ISSN: 1462-0324; 1462-0332
• DOI: 10.1093/rheumatology/kel419

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.