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Title: The role of novel transmembrane serine proteases : implications for arthritis
Author: Patel, Amit
ISNI:       0000 0004 2709 9944
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2011
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In the arthritides, the breakdown of articular cartilage and the erosion of subchondral bone lead to loss of efficient joint function. Matrix metalloproteinases (MMPs) can collectively degrade the extracellular matrix of cartilage, and have been strongly implicated in cartilage destruction. MMPs are produced as inactive precursors requiring activation. Addition of interleukin-1 (IL-1) and oncostatin M (OSM) to bovine cartilage in explant culture results in a synergistic loss of the collagen matrix, accompanied by a dramatic increase in pro-MMP synthesis and activation. Increasing evidence implicates serine proteinases in pathologic tissue turnover and the transmembrane serine proteases fibroblast activation protein-α (FAPα), dipeptidyl peptidase IV (DPPIV) and matriptase were recently found to be up-regulated in osteoarthritic (OA) cartilage compared to normal cartilage. The aim of this work was to identify whether these transmembrane serine proteases have roles in cartilage collagen breakdown. Inhibition of IL-1+OSM-mediated collagen breakdown was not observed using selective FAPα inhibitors, indicating that FAPα enzyme activity per se plays no direct role in collagen breakdown. In contrast, DPPIV inhibition showed significant protection of IL-1+OSM-mediated collagen breakdown. However, the mechanism of action of DPPIV remains to be elucidated. Matriptase was demonstrated to activate pro-MMPs as well as induce MMP expression in OA cartilage via protease-activated receptor 2 activation. This makes matriptase a key protease in the pathology of OA. Overall, this study has identified matriptase as a key serine protease in OA pathology and confirmed a potential role for DPPIV in cytokine-mediated cartilage degradation. These findings support the need for further research in order that therapeutic interventions targeting these enzymes may be realised.
Supervisor: Not available Sponsor: Medical Research Council ; Ferring Pharmaceuticals
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available