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Title: n-3 Polyunsaturated fatty acid effects on inflammatory mediator activity and intracellular signalling pathways in chondrocyte metabolism
Author: Hurst, Samantha
ISNI:       0000 0004 2747 138X
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2005
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Previous studies have shown that supplementation of n-3 polyunsaturated fatty acids (PUFAs) has a beneficial effect on reducing the expression and activity of degradative enzymes and inflammatory factors known to cause damage and destruction of cartilage in arthritic diseases. The aims of this thesis was to use a well-established in vitro model of cartilage degradation to further these studies and to investigate how n-3 PUFAs effect the expression of inflammatory factors at a proteomic level and to use specific inhibitors to identify possible signalling pathways involved in cartilage metabolism. The results of this thesis research indicate that n-3 PUFAs abrogate IL-1-induced cyclooxygenase-2 (COX-2) mRNA expression, protein levels and activity, measured as PGE2 production, in both normal bovine and human osteoarthritis articular cartilage chondrocytes. These studies were followed by the use of a simple array system to analyse the expression of several marker genes from different signalling pathways after IL-1 exposure, plus or minus n-3 PUFA supplementation. This led us to identify three possible pathways involved in IL-1-induced cartilage catabolism and inflammation. These were analysed further with the use of specific inhibitors to ascertain whether the inhibition profiles were similar to those seen by n-3 PUFAs. Two main pathways, the extracellular signal-regulated kinase (ERK) pathway and NFkappaB pathway were identified. Further analysis using the ERK pathway inhibitor, U0126, showed that it decreased IL-1-induced glycosaminoglycan release from the tissue, endogenous aggrecanase activity, ADAMTS-4 (but not ADAMTS-5) mRNA levels, MMP-3 and MMP-13 mRNA levels, COX-2 message, protein levels and PGE2 production in a manner similar to that seen with n-3 PUFA supplementation. Collectively, these results suggest that n-3 PUFAs may be directing their effects through the ERK pathway.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available