Adenoviral gene transfer into osteoarthritis synovial cells using the endogenous inhibitor IκBα reveals that most, but not all, inflammatory and destructive mediators are NFκB dependent

OBJECTIVES: Despite recent major advances in the understanding of the pathogenesis of rheumatoid arthritis, with tumour necrosis factor-alpha (TNF alpha ) established as a major therapeutic target, comparatively little is known about the mediators involved in the destructive and inflammatory pathways in osteoarthritis (OA). Recently, it has become appreciated that an inflammatory synovitis contributes not only to the signs and symptoms of osteoarthritis, but also to disease progression. Here, we use high-efficiency adenoviral gene transfer to investigate the role of the transcription factor nuclear factor- Kappa B (NF Kappa B) in regulating inflammatory and destructive mediators in the late stage OA synovium. METHODS: Infection with reporter adenoviruses transferring the {szligbeta}-galactosidase or green fluorescent protein genes verified that OA synovial cells could be infected (>95%). Adenovirus transferring the inhibitory subunit I Kappa B alpha inhibited NF Kappa B. The production of a whole array of pro- and anti-inflammatory cytokines and mediators, and several matrix metalloproteinases and their main inhibitor, was measured by enzyme-linked immunosorbent assay. RESULTS: The spontaneous production of macrophage-produced pro-inflammatory cytokines varied: TNF alpha was modestly inhibited by I Kappa B alpha overexpression, but interleukin (IL)-1 was unaffected. Both IL-6 and IL-8 were potently inhibited, as were granulocyte-macrophage colony stimulating factor and oncostatin M. Anti-inflammatory mediators like IL-10, the IL-1 receptor antagonist and the p55 soluble TNF receptor were unaffected. Matrix metalloproteinases 1, 3, 9 and 13 were potently inhibited by I Kappa B alpha overexpression, but not their main inhibitor tissue inhibitor of metalloproteinase-1. CONCLUSIONS: The OA synovium is a highly inflammatory environment, with spontaneous production of many cytokines and matrix metalloproteinases. Inhibition of NF Kappa B may have a beneficial effect on the balance between pro-inflammatory cytokines and anti-inflammatory mediators, and between destructive metalloproteinases and their main inhibitor.