Primary Supervisor: Yoshifumi Itoh (University of Oxford)
Secondary Supervisor: Miguel Pineda (University of Glasgow)
Joint Supervisors: Dominic Furniss (University of Oxford)
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. The functionality of cartilage is mainly relying on the nature of the major extracellular matrix components: type II collagen, that provides tissue architecture, and aggrecan, providing compression-resistant property to the tissue. In RA, these ECM components are degraded by proteolytic enzymes produced from synovial cells. We have previously identified MT1-MMP, a membrane-anchored collagenolytic metalloproteinase, as the responsible enzyme that destroys the cartilage by degrading collagen (1, 2, 3). Our study has shown that the treatment of arthritic mice with a selective inhibitor of MT1-MMP together with anti-TNF synergistically inhibited the progression of arthritis, suggesting that MT1-MMP-mediated cartilage destruction can be an excellent therapeutic target (3). Recently we discovered that one of the common coding single nucleotide polymorphisms (SNP) variant of MT1-MMP possesses significantly lower collagen degrading activity (around 17 % of wild-type MT1-MMP). Our study indicated that myofibroblasts carrying one allele of SNP express only 30% collagen degrading activity compared to the cells without the SNP allele, suggesting that carrying the one SNP allele is enough to reduce cellular collagen degrading activity significantly. Genome aggregation database indicates that around 35% of the European population carries at least one allele of this SNP. Since there is no correlation between the SNP and RA disease onset, it is expected that around 35% of RA patients are likely to carry the SNP allele, and we hypothesize that these patients may display milder disease phenotypes, i.e., cartilage erosion. This DPhil project will investigate these possibilities by utilizing cellular, genetic, and molecular techniques, and animal model of arthritis. The outcome of this project would contribute to the understanding of the effect of the SNP in RA development and may propose a novel means to predict the development of RA disease.
KEYWORDS: MT1-MMP, SNP, invasion, cartilage
TRAINING OPPORTUNITIES: 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 study. 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.
The student will be integrated in the RACE program, a multicenter network that connects The Kennedy Institute of Rheumatology with world leaders in the field of Rheumatology at the University of Birmingham, Newcastle and Glasgow. As part of the RACE initiative, the student will have the opportunity to attend to regular scientific meetings across the centers and to spend some time at the Institute of Infection, Immunity and Inflammation in Glasgow. As such, the project is highly innovative, and it represents the beginning of a new interdisciplinary approach.
Yoshifumi Itoh, PhD.
Associate Professor and PI of Cell Migration Group
The Kennedy Institute of Rheumatology
University of Oxford
Roosevelt Drive, Headington
Oxford, OX3 7FY
E-mail: [email protected]
1. Itoh Y. (2015) Membrane-type matrix metalloproteinase: their function and regulations. Matrix Biol. vol 44-46, pp207-23
2. 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
3. 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