Syndecan-3 in leukocyte extravasation and arthritis

Lead Research Organisation: Keele University
Department Name: Inst for Science and Tech in Medicine

Abstract

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.

Technical Summary

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.

Publications

10 25 50
 
Description BBSRC/CASE
Amount £88,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2013 
End 10/2017
 
Description GSK Project Grant
Amount £115,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 01/2006 
End 01/2009
 
Description Institute of Orthopaedics at Oswestry, Project grant
Amount £113,000 (GBP)
Organisation Institute of Orthopaedics 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2009 
End 01/2011
 
Description MRC DTC
Amount £94,928 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2012 
End 10/2016
 
Description MRC/ACORN studentship
Amount £51,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2009 
End 06/2012
 
Title An improved model of inflammation in skin 
Description A chemokine administration protocol has been signficantly improved in mouse skin to assess the effect of syndecan-3 gene deletion on inflammation. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact It allows us to assess the role of syndecan-3 in inflammation. 
 
Title synovial endothelial cells 
Description a method has been devised to extract synovial endothelail cells. These cells can be used for collaborators and ourselves to examine mechanisms of inflammation in vitro. 
Type Of Material Cell line 
Provided To Others? No  
Impact none yet 
 
Title synovial samples 
Description Samples rheumatoid synovium and cartilage have been collected from over 200 patients making a significant tissue bank. 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2006 
Provided To Others? Yes  
Impact about 20 papers have published using this material. 
 
Description Syndecan-3 expression 
Organisation University College Dublin
Country Ireland 
Sector Academic/University 
PI Contribution Defining syndecan-3 expression in arthritis
Collaborator Contribution providing clinically defined samples
Impact Publication
Start Year 2008
 
Description Use of phage display antibodies to detect specific heparan sulphte structures on syndecan 
Organisation Radboud University Nijmegen
Country Netherlands 
Sector Academic/University 
PI Contribution We have managed to demonstrate specific structures on syndecan-3 that may be involved in the presentation of chemokines to leukocytes. This then results in leukocyte migration into inflamed tissues.
Collaborator Contribution They generated phage display antibodies to specific glycosaminoglycan structures on syndecan
Impact One publication showing the presence of these structures on endothelial cells in inflamed tissues
Start Year 2008
 
Description syndecan-3 knock out mice 
Organisation Cleveland Clinic
Country United States 
Sector Charity/Non Profit 
PI Contribution Understanding the function of syndecan-3 in inflammation
Collaborator Contribution They provided syndecan-3 knock-out mice
Impact publication of research paper in Arthritis Research and Therapy
Start Year 2006
 
Description Charity talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Talk about our research to a patient and fund raising group

Interest in funding the research
Year(s) Of Engagement Activity 2010
 
Description Open Day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Talk about or research, practical demonstrations at a hospital open day


Increase in public awarness
Year(s) Of Engagement Activity 2007
 
Description Open day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Talk about or research, practical demonstrations at a hospital open day


Increase in public awarness
Year(s) Of Engagement Activity 2008
 
Description Open day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Talk about or research, practical demonstrations at a hospital open day

Increase in public awarness
Year(s) Of Engagement Activity 2009
 
Description Open day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Talk about or research, practical demonstrations at a hospital open day

Increase in public awarness
Year(s) Of Engagement Activity 2009
 
Description Open day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Talk about or research, practical demonstrations at a hospital open day



Increase in public awarness
Year(s) Of Engagement Activity 2007
 
Description Research Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact A day when members of the public visit our labs and see the research

The public had an increased understanding of our research
Year(s) Of Engagement Activity 2007,2008,2009
 
Description Research Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact 50 local members of the public and profesional scienstists attended talks and poster sessions, and were shown around the labs.

Local fund raisers donated funds for our research.
Year(s) Of Engagement Activity 2010
 
Description School visit - Oswestry 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact They heard about the research and performed some hands-on experiments

They generated further interest in science and pathology
Year(s) Of Engagement Activity 2009