Rheumatoid arthritis (RA) is a systemic inflammatory disease, the hallmark of which is the destruction of the joint tissues where inflamed synovial tissue invades and destroys cartilage and bone leading to disability. Functionality of cartilage largely relyies on the nature of the major extracellular matrix components: type II collagen and aggrecan, where collagen provides tissue architecture and aggrecan provides compression resistance. In RA, these ECM components are degraded by proteolytic enzymes produced from synovial cells and we have previously identified the membrane-anchored collagenolytic metalloproteinase, MT1-MMP, as the enzyme responsible for causing invasion of synovial tissue into cartilage (1, 2, 3). Our study has shown that treatment of arthritic mice with a selective inhibitor of MT1-MMP together with anti-TNF synergistically inhibited progression of arthritis, suggesting that MT1-MMP-mediated cartilage destruction is a good therapeutic target (3). In synovial tissue MT1-MMP is highly expressed in synovial fibroblasts that directly make contact with cartilage. This pattern of MT1-MMP expression is likely to be due to stimulation of the synovial fibroblasts by cartilage collagen, and we identified the collagen tyrosine kinase receptor, DDR2, as the mediator of collagen signaling to upregulate MT1-MMP expression and promote its function in synovial fibroblasts (4). Interestingly, healthy intact cartilage does not activate DDR2, and cartilage needs to be partially damaged by other proteolytic enzymes to induce DDR2-mediated MT1-MMP expression, suggesting that there are other proteolytic events that convert cartilage matrix to a stimulator of tissue destruction (4). Therefore, identification of the processes involved in transformation of cartilage matrix during development of arthritis is important to understand the pathogenesis of RA.
Furthermore, by identifying the in vivo role of DDR2 in animal model of arthritis, we will be able to identify DDR2 inhibition as a novel therapeutic strategy to improve treatment of the RA patients especially those who do not receive adequate benefit from anti-cytokine therapies (around 50% of all RA patients). This DPhil project will tackle those important problems by utilizing cellular and molecular techniques and animal model of arthritis.
The Kennedy Institute is a world-renowned research centre and is housed in a state-of-the-art research facility. Full training will be provided in a range of cell and molecular biology techniques and animal studies. A core curriculum of 20 lectures will be taken in the first term of year 1 to provide a solid foundation in musculoskeletal sciences, immunology and data analysis. Students will attend weekly departmental meetings and will be expected to attend seminars within the department and those relevant in the wider University. Subject-specific training will be received through our group's weekly supervision meetings. Students will also attend external scientific conferences where they will be expected to present the research findings.
Itoh Y. (2015) Membrane-type matrix metalloproteinase: their function and regulations. Matrix Biol. vol 44-46, pp207-23
Miller, M. C., Manning, H. B., Jain, A., Troeberg, L., Dudhia, J., Essex, D., Sandison, A., Seiki, M., Nanchahal, J., Nagase, H., and Itoh, Y. (2009) Membrane-type 1 matrix metalloproteinase is a crucial promoter of synovial invasion in human rheumatoid arthritis. Arthritis Rheum 60, 686-697
Kaneko K, Williams RO, Dransfield DT, Nixon AE, Sandison A and Itoh Y (2016) Selective inhibition of membrane type 1 matrix metalloproteinase abrogates progression of inflammatory arthritis: synergy with TNF blockade. Arthritis Rheum 68 (2), 521-531
Majkowska I, Shitomi Y, Ito N, Gray NS, Itoh Y (2017) Discoidin Domain Receptor 2 Mediates Collagen-Induced Activation of Membrane-Type 1 Matrix Metalloproteinase in Human Fibroblasts. J Biol Chem, 292(16):6633-6643