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Title: Metalloproteinase gene expression and its control in osteoarthritis
Author: Davidson, Rosemary Karen
ISNI:       0000 0004 2671 2954
Awarding Body: University of East Anglia
Current Institution: University of East Anglia
Date of Award: 2008
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Osteoarthritis (OA) is the most common arthritic condition. It is a debilitating disease of the joints, characterised by articular cartilage degradation. Effective, disease-modifying drugs are not currently available for the treatment ofOA. Matrix metalloproteinase (MMP) and a disintegrin, a metalloproteinase and a thrombospondin motif (ADAMTS) proteases are capable of degrading all components of the extracellular matrix (ECM). Their activities are normally balanced by tissue inhibitors of metalloproteinases (TIMPs). Together MMPs, ADAMTSs and TIMPs regulate the normal turnover of extracellular matrix. Unbalanced proteolysis of the cartilage ECM is central to the current dogma of OA pathogenesis. This thesis profiled the expression of all human MMP, ADAMTS and TIMP genes in synovium and cartilage tissues, comparing OA and control samples. This has provided a comprehensive picture of proteolysis in the joint. Using TaqMan® low-density array technology (TLDA), these samples were then profiled for the expression of 268 cytokines and their receptors, to delineate important and novel factors involved in the control ofmetalloproteinase expression in OA. In OA synovium, the genes with the most significantly increased expression were MMP28, ADAMTSJ6, ADAMTS17 and TIMP2. MMPJO, ADAMTS4 and ADAMTS9 were the genes with the most significantly decreased expression. TLDA data revealed a potential increase in TNFSFll signalling in OA cartilage. Recombinant human TNFSFll (rhTNFSFll) stimulation assays were carried out in chondrocytes. rhTNFSFll regulated the expression of TNFRSFllB, RANTES, Collagen XAJ, iNOS, NFATc1, TRAF6 and c-fos. Interestingly, rhTNFSFll also increased the expression of MMPI, MMP3, and MMPJ3 in primary chondrocytes and MMP13 and ADAMTSJ6 in C281I2 immortalised chondrocytes. rhTNFSFll stimulation did not activate p50 or p65 NF-KB subunits or MAPKs in primary chondrocytes. TNFSFll is able to signal in primary chondrocytes, however, the pathway and mechanism remains to be clarified.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available