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Adenoviral gene transfer of the endogenous inhibitor IkappaBalpha into human osteoarthritis synovial fibroblasts demonstrates that several matrix metalloproteinases and aggrecanases are nuclear factor-kappaB-dependent

Bondeson, Jan, Lauder, Sarah Nicol, Wainwright, Shane Daniel, Amos, Nick, Evans, A., Hughes, Clare Elizabeth, Feldmann, M. and Caterson, Bruce 2007. Adenoviral gene transfer of the endogenous inhibitor IkappaBalpha into human osteoarthritis synovial fibroblasts demonstrates that several matrix metalloproteinases and aggrecanases are nuclear factor-kappaB-dependent. The Journal of Rheumatology 34 (3) , pp. 523-533.

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Abstract

OBJECTIVE: To investigate the role of the transcription factor nuclear factor-kB (NF-kappaB) in promoting inflammatory and destructive responses in human osteoarthritis (OA) synovial fibroblasts, by assessing the effect of NF-kappaB blockade on the production of cytokines and destructive enzymes. METHODS: Infection with adenoviruses transferring the beta-galactosidase gene was used to ascertain that the OA fibroblasts could be infected (> 95%). Using an adenovirus transferring the inhibitory subunit IkappaBa, effective inhibition of NF-kappaB was achieved. The expression and production of several pro- and antiinflammatory cytokines and mediators, the major matrix metalloproteinases (MMP 1, 3, and 13), their main inhibitor tissue inhibitor of metalloproteinase-1 (TIMP-1), and the aggrecanases (ADAMTS4 and ADAMTS5) were measured by ELISA and/or reverse transcription-polymerase chain reaction, and their dependence on NF-kappaB evaluated. RESULTS: The production of interleukin 6 (IL-6), monocyte chemoattractant protein-1, and RANTES was potently inhibited by IkBa overexpression, irrespective of stimulus, but IL-8 was unaffected. The p55 soluble tumor necrosis factor (TNF) receptor was unaffected, but the p75 soluble TNF receptor was potently inhibited by IkBa overexpression. MMP-1, MMP-3, and MMP-13 were inhibited by IkappaBa overexpression, at both the mRNA and protein levels, whereas TIMP-1 was unaffected. The mRNA gene expression of ADAMTS4 was also inhibited by IkappaBa overexpression, particularly in IL-1-stimulated cells, but ADAMTS5 was unaffected. CONCLUSION: In OA synovial fibroblasts, inhibition of NF-kappaB has a beneficial effect on the balance between the expression of proinflammatory cytokines and antiinflammatory mediators. Inhibition of this transcription factor also results in the decreased expression of several destructive metalloproteinases and also the ADAMTS4 aggrecanase.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > R Medicine (General)
Uncontrolled Keywords: ADAM Proteins/metabolism* Adenoviridae Aged Aged, 80 and over Cells, Cultured Female Fibroblasts/enzymology Fibroblasts/immunology* Fibroblasts/metabolism Genetic Vectors Humans Inflammation Mediators/metabolism* Male Matrix Metalloproteinases/metabolism* Middle Aged NF-kappa B/antagonists & inhibitors NF-kappa B/immunology* Osteoarthritis/physiopathology* Procollagen N-Endopeptidase/metabolism* Synovial Membrane/cytology Synovial Membrane/metabolism Tissue Inhibitor of Metalloproteinase-1/metabolism
ISSN: 0315-162X
Last Modified: 12 Jun 2019 02:19
URI: http://orca-mwe.cf.ac.uk/id/eprint/195

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