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

Amos, Nick, Lauder, Sarah Nicol, Evans, A., Feldmann, M. and Bondeson, Jan 2006. Adenoviral gene transfer into osteoarthritis synovial cells using the endogenous inhibitor IkappaBalpha reveals that most, but not all, inflammatory and destructive mediators are NFkappaB dependent. Rheumatology 45 (10) , pp. 1201-1209. 10.1093/rheumatology/kel078

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Abstract

Objectives. Despite recent major advances in the understanding of the pathogenesis of rheumatoid arthritis, with tumour necrosis factor-alpha (TNF) 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-B (NFB) in regulating inflammatory and destructive mediators in the late stage OA synovium. Methods. Infection with reporter adenoviruses transferring the β-galactosidase or green fluorescent protein genes verified that OA synovial cells could be infected (>95%). Adenovirus transferring the inhibitory subunit IB inhibited NFB. 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 was modestly inhibited by IB 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 IB 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 NFB may have a beneficial effect on the balance between pro-inflammatory cytokines and anti-inflammatory mediators, and between destructive metalloproteinases and their main inhibitor.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Uncontrolled Keywords: Adenovirus ; Fibroblast ; Interleukin-1 ; Macrophage ; Matrix metalloproteinase ; NF-kappa-B, Osteoarthritis ; Synovium ; Tumour necrosis factor
ISSN: 1460-2172
Last Modified: 12 Jun 2019 02:19
URI: http://orca.cf.ac.uk/id/eprint/327

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