Skip to main content
  • Poster presentation
  • Open access
  • Published:

Inhibition of Syndecan-4 by therapeutic antibodies reduces TNFα dependent joint destruction in mice

Background

Syndecan-4, a member of a syndecan family of transmembrane heparansulfate proteoglycans has been recently associated with cell-matrix-adhesion, cell-migration, differentiation and proliferation, but its specific function in inflammatory pathologies remains unclear. We used the human TNFalpha transgenic mouse (hTNFtg) to analyse the expression and function of syndecan-4 in chronic-destructive-arthritis and answer the question whether inhibition of syndecan-4 by specific antibodies may prevent cartilagedestruction and/or improve the phenotype after onset of the disease in this animal model of human RA.

Methods

Expression of syndecan-4 was investigated by immunohistochemistry in the hind-paws of 8-weeks/12-weeks old hTNFtg mice and wild type controls. In addition, synovial fibroblasts were isolated and analysed for syndecan-4-expression by RT-PCR. For functional analyses, we generated blocking-antibodies against syndecan-4. To investigate their effect on TNFalpha mediated-destructive-arthritis, hTNFtg mice were injected with the antibodies or with IgG-control twice weekly for 4-weeks in a preventive manner (age-4-to-8-weeks) and for disease treatment of joint destruction (age-8-to-12-weeks) into their hind paws. Evaluation of disease severity included clinical parameters (weight, arthritis-score, grip-strength) as well as histomorphometric analysis of toluidin-blue-stained paraffin sections.

Results

As seen in immunohistochemistry, there was a strong expression of syndecan-4 in the synovial membranes of hTNFtg mice, whereas only negligible staining for syndecan-4 was found in synovial tissues of wild type animals. In vitro, synovial fibroblasts isolated from hTNFtg mice showed more than 30-fold higher expression of syndecan-4 than wild type controls. Administration of the anti-syndecan-4 antibodies but not of IgG-control in preventive treated 4-week-old hTNFtg mice clearly ameliorated the clinical signs of arthritis and protected the treated joints from cartilage damage. At histomorphometric analysis, this was evident for all analysed parameters but seen most prominently for area of distained cartilage.

Significantly reduced cartilage damage in the anti-syndecan-4 treated hTNFtg mice was accompanied by a striking reduction in the expression of MMP-3. The treatment with antisyndecan-4 in 8-week-old hTNFtg mice after onset of arthritis clearly ameliorated the jointdestruction, and improved cartilage-damage. The treatment also showed a clear reduction of inflammation in the paws compared to the untreated animals.

Conclusions

Our findings indicate that syndecan-4 is involved prominently in fibroblast-mediated cartilagedamage in hTNFtg mice by regulating the exression of disease-relevant MMPs. More importantly, the data suggest that inhibition of syndecan-4 not only prevens cartilage damage, but also reduces the severity after onset of the disease.

Author information

Authors and Affiliations

Authors

Rights and permissions

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article

Stratis, A., Neugebauer, K., Frohling, M. et al. Inhibition of Syndecan-4 by therapeutic antibodies reduces TNFα dependent joint destruction in mice. Arthritis Res Ther 14 (Suppl 1), P64 (2012). https://doi.org/10.1186/ar3665

Download citation

  • Published:

  • DOI: https://doi.org/10.1186/ar3665

Keywords