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Open Access Highly Accessed Research article

Syndecan-3 is selectively pro-inflammatory in the joint and contributes to antigen-induced arthritis in mice

Oksana Kehoe1, Neena Kalia2, Sophie King3, Andrew Eustace3, Charlotte Boyes3, Ofer Reizes4, Anwen Williams5, Angela Patterson6 and Jim Middleton13*

Author Affiliations

1 Leopold Muller Arthritis Research Centre, Medical School, ISTM, Keele University, RJAH Orthopaedic Hospital, Oswestry SY10 7AG, UK

2 Centre for Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK

3 Faculty of Medicine and Dentistry, School of Oral and Dental Sciences, Lower Maudlin Street, University of Bristol, Bristol BS1 2LY, UK

4 Lerner Research Institute, 9500 Euclid Avenue, Cleveland OH 44195, USA

5 Department of Rheumatology, University of Wales College of Medicine, Heath Park, Cardiff CF14 4YS, UK

6 Rowett Institute of Nutrition and Health, University of Aberdeen, Greenburn Road, Aberdeen AB21 9SB, UK

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Arthritis Research & Therapy 2014, 16:R148  doi:10.1186/ar4610

Published: 11 July 2014

Abstract

Introduction

Syndecans are heparan sulphate proteoglycans expressed by endothelial cells. Syndecan-3 is expressed by synovial endothelial cells of rheumatoid arthritis (RA) patients where it binds chemokines, suggesting a role in leukocyte trafficking. The objective of the current study was to examine the function of syndecan-3 in joint inflammation by genetic deletion in mice and compare with other tissues.

Methods

Chemokine C-X-C ligand 1 (CXCL1) was injected in the joints of syndecan-3−/−and wild-type mice and antigen-induced arthritis performed. For comparison chemokine was administered in the skin and cremaster muscle. Intravital microscopy was performed in the cremaster muscle.

Results

Administration of CXCL1 in knee joints of syndecan-3−/−mice resulted in reduced neutrophil accumulation compared to wild type. This was associated with diminished presence of CXCL1 at the luminal surface of synovial endothelial cells where this chemokine clustered and bound to heparan sulphate. Furthermore, in the arthritis model syndecan-3 deletion led to reduced joint swelling, leukocyte accumulation, cartilage degradation and overall disease severity. Conversely, CXCL1 administration in the skin of syndecan-3 null mice provoked increased neutrophil recruitment and was associated with elevated luminal expression of E-selectin by dermal endothelial cells. Similarly in the cremaster, intravital microscopy showed increased numbers of leukocytes adhering and rolling in venules in syndecan-3−/−mice in response to CXCL1 or tumour necrosis factor alpha.

Conclusions

This study shows a novel role for syndecan-3 in inflammation. In the joint it is selectively pro-inflammatory, functioning in endothelial chemokine presentation and leukocyte recruitment and cartilage damage in an RA model. Conversely, in skin and cremaster it is anti-inflammatory.