Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


S100A4 as a Novel Mediator of TGF- Driven Dermal Fibrosis in Systemic Sclerosis.

Tomcik4,  Michal, Zerr2,  Pawel, Palumbo2,  Katrin, Furnrohr2,  Barbara G., Avouac3,  Jerome, Horn2,  Angelika, Dees2,  Clara

Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Switzerland
Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany and Paris Descartes University, Rheumatology A Department Cochin Hospital, Paris, France
Department of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany and Institute of Rheumatology and Connective Tissue Research Laboratory, Department of Rheumatology of the First Faculty of Medicine, Charles U
Friedrich Alexander Univ, Erlangen, Germany
Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark
Institute of Rheumatology and Connective Tissue Research Laboratory, Department of Rheumatology of the First Faculty of Medicine, Charles University in Prague, Czech Republic
University of Erlangen, Erlangen, Germany

Background:

S100A4 (metastasis associated protein) is a calcium binding protein exerting regulatory functions in diverse biological processes. It promotes cancer progression and metastasis by regulating the remodelling of the extracellular matrix.

Objectives:

The aim of this study was to investigate the contribution of S100A4 to the pathologic activation of fibroblasts in SSc and its role in the development of a fibrotic phenotype in a mouse model of experimental dermal fibrosis.

Methods:

Activation of S100A4 in human skin and experimental dermal fibrosis was determined by real-time PCR, immunohistochemistry and western blot. Collagen synthesis of SSc and healthy dermal fibroblasts was quantified by real-time PCR and SirCol collagen assay. Bleomycin-induced dermal fibrosis, a model for early, inflammatory stages of SSc, was used to assess the role of S100A4 in vivo using mice deficient for S100A4 (-/-) and wildtype littermates (+/+).

Results:

Increased expression of S100A4 was detected in the upper layer of the dermis of SSc patients and was clearly colocalized with alpha-smooth muscle actin-positive fibroblasts. The overexpression of S100A4 persisted in cultured SSc fibroblasts and might contribute to their activated phenotype. A similar increase in S100A4 expression was observed in the skin samples from mice challenged with bleomycin and tsk-1 mice, both on mRNA (3.5- and 15.5-fold increase, respectively) and protein level. TGF-b stimulation of both healthy and SSc fibroblasts led to an increased expression of S100A4 protein. Of particular interest, knockdown of S100A4 by siRNA fully abrogated the stimulatory effects of TGF-b on the collagen synthesis of SSc fibroblasts. In agreement with the role of S100A4 as a novel mediator of the pro-fibrotic effects of TGF-b, mice lacking S100A4 were protected from experimental fibrosis. In the model of bleomycin-induced dermal fibrosis, inhibition of S100A4 decreased dermal thickening by 53±2% (p<0.01), significantly reduced the hydroxyproline content by 30±4% (p<0.01) and the number of myofibroblasts by 254±16% (p<0.01). Reduced induction of dermal fibrosis in S100A4 -/- mice might result from inhibition of TGF-b signaling as evidenced by reduced nuclear accumulation of phosphorylated Smad 3 in the skin sections of S100A4 -/- mice treated with bleomycin compared to their wildtype (+/+) littermates.

Conclusion:

This is the first study reporting on the role of S100A4 in SSc. We demonstrate an upregulation of S100A4 in SSc in a TGF-b dependent manner, and that inhibition of S100A4 reduces collagen synthesis in activated SSc fibroblasts. Knockdown of S100A4 protected from fibrosis in the murine model of bleomycin-induced dermal fibrosis due to inhibition of TGF-b signaling. Thus, the S100A4 pathway could be an interesting novel target for the treatment of SSc.

To cite this abstract, please use the following information:
Tomcik, Michal, Zerr, Pawel, Palumbo, Katrin, Furnrohr, Barbara G., Avouac, Jerome, Horn, Angelika, et al; S100A4 as a Novel Mediator of TGF- Driven Dermal Fibrosis in Systemic Sclerosis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :614
DOI: 10.1002/art.28382

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