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Investigating the role of NF-kappaB in the pathology of osteoarthritis

Lauder, Sarah Nicol 2007. Investigating the role of NF-kappaB in the pathology of osteoarthritis. PhD Thesis, Cardiff University.

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Globally the most prevalent muscoskeletal condition affecting humans, osteoarthritis is a complex, multifactorial disease characterised by deterioration of articular cartilage and varying degrees of synovial inflammation. The catabolic cytokine interleukin-1beta (IL-1beta), a potent inducer of the transcription factor NFkappaB, induces the production of cartilage destructive aggrecanases and matrix metalloproteinases (MMPs) and the inflammatory cytokine, interleukin-6 (IL-6), within the joint. The aim of the work described in this thesis was to investigate the role of NFkappaB within the osteoarthritic joint and its potential as a therapeutic target for disease intervention. NFkappaB activation was inhibited using adenoviral gene transfer or by two novel pharmacological inhibitors of IKK, R0100 and R0919. Inhibition of the NFkappaB signalling cascade in human synovial fibroblasts from osteoarthritic patients suppressed the IL-1beta induction of IL-6, MMP-1 and MMP-3 but did not affect the levels of tissue inhibitor of metalloproteinases-1 (TIMP-1). To further investigate the effects of these IKK inhibitors, cartilage degradation was investigated by culturing murine patellas with human synovial fibroblasts. Early stage cartilage deterioration, induced by IL-1beta, was prevented by NFkappaB inhibition. An animal model of OA, that reflected the early stage pathological changes, was set up as part of this study. The therapeutic efficacy of RO100 and R0919 was tested in vivo. It was observed that neither inhibitor prevented pathological changes associated with OA, for example cartilage degradation. The basis of the lack of efficacy demonstrated by RO100 and R0919 is unknown but may be due to poor bioavailability of the agents within the joint. In conclusion, the studies conducted during this thesis have shown, in various systems, that inhibiting NFkappaB can prevent changes such as cartilage degradation that occur in OA. Increasing the bioavailability of these or other inhibitors of NFkappaB may be key in the development of successful novel therapeutic modalities in the future.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
ISBN: 9781303181726
Funders: Arthritis Research UK, Cardiff University School of Medicine
Date of First Compliant Deposit: 30 March 2016
Last Modified: 04 Jun 2017 06:00

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