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S100A4 amplifies TGF-β-induced fibroblast activation in systemic sclerosis
  1. Michal Tomcik1,2,
  2. Katrin Palumbo-Zerr1,
  3. Pawel Zerr1,
  4. Jerome Avouac3,
  5. Clara Dees1,
  6. Barbora Sumova1,2,
  7. Alfiya Distler1,
  8. Christian Beyer1,
  9. Lucie Andres Cerezo2,
  10. Radim Becvar2,
  11. Oliver Distler4,
  12. Mariam Grigorian5,
  13. Georg Schett1,
  14. Ladislav Senolt2,
  15. Jörg H W Distler1
  1. 1Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Department of Rheumatology, 1st Faculty of Medicine, Institute of Rheumatology, Charles University, Prague, Czech Republic
  3. 3Rheumatology A Department, Paris Descartes University, Cochin Hospital, Paris, France
  4. 4Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital, Zurich, Switzerland
  5. 5Neuro-Oncology Group, Faculty of Health Sciences, Institute of Neuroscience and Pharmacology, Copenhagen University, Copenhagen, Denmark
  1. Correspondence to Jörg H W Distler, Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen D-91054, Germany; joerg.distler{at}


Objectives S100A4 is a calcium binding protein with regulatory functions in cell homeostasis, proliferation and differentiation that has been shown to promote cancer progression and metastasis. In the present study, we evaluated the role of S100A4 in fibroblast activation in systemic sclerosis (SSc).

Methods The expression of S100A4 was analysed in human samples, murine models of SSc and in cultured fibroblasts by real-time PCR, immunohistochemistry and western blot. The functional role of S100A4 was evaluated using siRNA, overexpression, recombinant protein and S100A4 knockout (S100A4−/−) mice. Transforming growth factor β (TGF-β) signalling was assessed by reporter assays, staining for phosphorylated Smad2/3 and analyses of target genes.

Results The expression of S100A4 was increased in SSc skin and in experimental fibrosis in a TGF-β/Smad-dependent manner. Overexpression of S100A4 or stimulation with recombinant S100A4 induced an activated phenotype in resting normal fibroblasts. In contrast, knockdown of S100A4 reduced the pro-fibrotic effects of TGF-β and decreased the release of collagen. S100A4−/− mice were protected from bleomycin-induced skin fibrosis with reduced dermal thickening, decreased hydroxyproline content and lower myofibroblast counts. Deficiency of S100A4 also ameliorated fibrosis in the tight-skin-1 (Tsk-1) mouse model.

Conclusions We characterised S100A4 as a downstream mediator of the stimulatory effects of TGF-β on fibroblasts in SSc. TGF-β induces the expression of S100A4 to stimulate the release of collagen in SSc fibroblasts and induce fibrosis. Since S100A4 is essentially required for the pro-fibrotic effects of TGF-β and neutralising antibodies against S100A4 are currently evaluated, S100A4 might be a candidate for novel antifibrotic therapies.

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