Investigation of DDR2 signalling that promotes synovial cell invasion into cartilage in rheumatoid arthritis

Project overview

A hallmark of rheumatoid arthritis (RA) is the destruction of cartilage and bone by inflamed synovial pannus tissue. The primary cell type that erodes cartilage in RA is synovial fibroblasts (RASF), and we have previously identified the crucial cartilage-eroding proteolytic enzyme, membrane-type 1 matrix metalloproteinase (MT1-MMP), which is highly expressed on the cell surface of RASF (Miller et al., 2009). Inhibition of MT1-MMP completely abolished cartilage invasion of RASF, and selective inhibition of MT1-MMP in a mouse model of arthritis also inhibited cartilage degradation (Kaneko et al., 2016).

MT1-MMP is highly expressed in the RASF at the interface between the pannus and cartilage, suggesting that cartilage may stimulate RASF to express MT1-MMP (Miller et al., 2009). We found that a collagen receptor tyrosine kinase, discoidin domain receptor 2 (DDR2), mediates cartilage collagen signal to synovial fibroblasts and upregulates the MT1-MMP gene (Majkowska et al., 2017). Interestingly, intact healthy cartilage does not activate the DDR2 signal, and cartilage needs to be partially damaged to activate DDR2 in an efficient manner. These findings suggest that DDR2 acts as a sensor detecting cartilage damage. In addition to MT1-MMP gene upregulation, DDR2 signalling also plays a role in regulating MT1-MMP function. Pharmacological inhibition of DDR2 inhibited MT1-MMP activity in RASF, although MT1-MMP is still expressed (Majkowska et al., 2017). These data suggest that the role of DDR2 signalling is not only in MT1-MMP gene upregulation but also modulates other gene expressions to activate synovial cells for tissue destruction.

Recently it was reported that DDR2 contributes to the progression of arthritis by upregulating IL-15 and Dkk-1 in the mouse model of arthritis. A lack of DDR2 and pharmacological inhibition of DDR2 abrogates joint damage in the mouse model of arthritis (Mu et al., Arthritis & Rheum, 2020), which supports our hypothesis of a broader role of DDR2 signalling. However, the mechanism of DDR2 signalling to activate synovial fibroblasts needs further understanding, and a systematic approach to unveil the role of DDR2 signalling is required.

This DPhil project aims to reveal the whole picture of DDR2 signalling and its effects that promote synovial cell invasion. To achieve the goal, we have the following four specific aims.

1. Identify the complete set of genes that DDR2 signalling activates in human synovial fibroblasts by RNAseq;
2. Investigate the roles of the identified genes in the synovial invasion;
3. Investigate the mechanism of DDR2 activation by cartilage;
4. Investigate the expression of the identified genes in the human RA and mouse model of arthritis.

Achieving this DPhil project would significantly deepen our understanding of RA disease progression and may identify novel means to prevent cartilage degradation in RA.

keywords

Rheumatoid Arthritis, Cartilage, DDR2, MT1-MMP, invasion

training opportunities

The Kennedy Institute is a world-renowned research centre housed in a state-of-the-art research facility. Full training will be provided in a range of cell and molecular biology techniques. 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.

key publications

1. Gifford, V., and Itoh, Y. (2019) MT1-MMP-dependent cell migration: proteolytic and non-proteolytic mechanisms. Biochem Soc Trans, 47 (3), 811-826
2. Itoh, Y. (2018) Discoidin domain receptors: Microenvironment sensors that promote cellular migration and invasion. Cell Adh Migr. 12 (4), 378-385
3. 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
4. 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
5. Miller MC, Manning HB, Jain A, Troeberg L, Dudhia J, Essex D, Sandison A, Seiki M, Nanchahal J, Nagase H, Itoh Y (2009) Membrane type 1 matrix metalloproteinase is a crucial promoter of synovial invasion in human rheumatoid arthritis. Arthritis Rheum 60(3): 686-697

contact information of all supervisors

Y. Itoh: yoshi.itoh@kennedy.ox.ac.uk

C. Buckley: christopher.buckley@kennedy.ox.ac.uk

R. Williams: richard.williams@kennedy.ox.ac.uk