Syndecan-3 in leukocyte extravasation and arthritis

Rheumatoid arthritis in a common, debilitating and painful disease affecting about 1% of the population and can result in increased mortality. Migration of leukocytes (white cells) from the blood into rheumatoid joints is enhanced by molecules called chemokines. Carbohydrates on the endothelial cells that line blood vessels bind chemokines and present chemokines to leukocytes in the blood. We have found that a particular carbohydrate-bearing molecule, syndecan-3, on the endothelial cells in rheumatoid arthritis binds the chemokine CXCL8. The project aim is to elucidate the importance of syndecan-3-chemokine interactions in rheumatoid arthritis. This will be carried out by studying mice that do not possess syndecan-3. The migration of leukocytes into tissues will be studied in syndecan-3 deleted mice to examine if this differs compared to normal animals. In addition, it will be determined if the severity of arthritis in these mice is altered compared to normal. Therefore this work could lead to greater understanding of disease mechanisms in rheumatoid arthritis and targeting syndecan-3 could ultimately be used as a new type of treatment.
The research work will be presented at our annual hospital open day. This day is advertised widely and the general public and scientific professionals visit the laboratories and hear about the medical research being carried out in the hospital and medical school. In addition, we have groups of school pupils come and view the work we perform in order to foster an interest in science. When grants are awarded to our research centre an article is written for the local newspaper (The Shropshire Star) describing the research in lay terms. Furthermore, at a later date the results of the research would be published in popular journals and local or national newspapers as appropriate. All these lay communication activities are part of an existing programme and will not incur extra costs.
The work would also be presented to the scientific community and health professionals at congresses in terms of oral and poster presentations, and in written form in published peer-reviewed journals.

Chemokines enhance the migration of blood leukocytes into the synovium in rheumatoid arthritis (RA). There is evidence that endothelial heparan sulphate proteoglycan (HSPG) is involved in transcytosing and presenting chemokines to blood leukocytes, resulting in leukocyte extravasation into the tissue. We have evidence that a particular endothelial HSPG, syndecan-3, binds the chemokine CXCL8 (IL-8) in the rheumatoid synovium. The overall aim of the project is to examine the functional role of syndecan-3 in leukocyte extravasation and the initiation and progression of arthritis. Using syndecan-3 gene deleted mice it will be investigated if leukocyte migration into the skin in response to chemokines is altered compared to wild-type animals. It will be elucidated if leukocyte firm adhesion, which is triggered by chemokines, is altered in syndecan-3 null mice using intravital microscopy. Furthermore, an antigen-induced arthritis model will be performed in these knock-out mice to determine if leukocyte infiltration into the joint and disease severity are influenced and if the effects are chemokine-related. The purpose of the study is to test the hypothesis that endothelial syndecan-3-chemokine interactions are important in regulating leukocyte extravasation and the pathophysiology of arthritis. The successful outcome of the study will further the understanding of chronic inflammatory disease and identify syndecan-3 as a potential therapeutic target in RA, leading ultimately to potential benefits in terms of improving human health.