title: Interleukin-1beta induced activation of nuclear factor-kappab can be inhibited by novel pharmacological agents in osteoarthritis.
abstract: OBJECTIVE
  To investigate the importance of activation of the transcription factor, nuclear factor-kappaB (NF-kappaB) by interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) 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-1beta, TNF-alpha and NF-kappaB 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-kappaB by a novel agent, RO100 at a dose of 0.1 microM, 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-1beta and TNF-alpha neutralizing antibodies in OA-COCUL.
  
  
  CONCLUSIONS
  We have demonstrated that a novel pharmacological inhibitor of NF-kappaB, RO100 inhibits pathological mediators of OA progression with equivalent efficacy as established IL-1beta and TNF-alpha neutralizing strategies. Our findings highlight a potential for developing NF-kappaB targeted therapeutics for positively regulating disease activity and improving clinical outcome in OA.
authors.affiliation: Rheumatology Research Laboratory, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. LauderSN@cardiff.ac.uk
authors.forename: S N
authors.initials: SN
authors.lastname: Lauder
authors.forename: S M
authors.initials: SM
authors.lastname: Carty
authors.forename: C E
authors.initials: CE
authors.lastname: Carpenter
authors.forename: R J
authors.initials: RJ
authors.lastname: Hill
authors.forename: F
authors.initials: F
authors.lastname: Talamas
authors.forename: J
authors.initials: J
authors.lastname: Bondeson
authors.forename: P
authors.initials: P
authors.lastname: Brennan
authors.forename: A S
authors.initials: AS
authors.lastname: Williams
mesh_terms: D018501:Antirheumatic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D018920:Coculture Techniques; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010003:Osteoarthritis / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*
chemical_list: D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1; D000068800:Etanercept