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The transcription factor JunD mediates transforming growth factor β-induced fibroblast activation and fibrosis in systemic sclerosis
  1. Katrin Palumbo1,
  2. Pawel Zerr1,
  3. Michal Tomcik1,2,
  4. Stefan Vollath1,
  5. Clara Dees1,
  6. Alfiya Akhmetshina1,
  7. Jerome Avouac1,3,4,
  8. Moshe Yaniv5,
  9. Oliver Distler6,
  10. Georg Schett1,
  11. Jörg H W Distler1
  1. 1Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Department of Rheumatology of the First Faculty of Medicine, Institute of Rheumatology and Connective Tissue Research Laboratory, Charles University in Prague, Prague, Czech Republic
  3. 3Rheumatology A Department, Paris Descartes University, Cochin Hospital, Paris, France
  4. 4INSERM U781, Necker Hospital, Paris, France
  5. 5Developmental Biology, Institut Pasteur, Paris, France
  6. 6Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland
  1. Correspondence to Jörg H W Distler, Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Universitätsstrasse 29, Erlangen D-91054, Germany, joerg.distler{at}uk-erlangen.de

Abstract

Objectives Transforming growth factor β (TGFβ) has been identified as a key player in fibrotic diseases. However, the molecular mechanisms by which TGFβ activates fibroblasts are incompletely understood. Here, the role of JunD, a member of the activator protein 1 (AP-1) family of transcription factors, as a downstream mediator of TGFβ signalling in systemic sclerosis (SSc), was investigated.

Methods The expression of JunD was analysed by real-time PCR, immunofluorescence, western blotting and immunohistochemistry. The canonical Smad pathway was specifically targeted by small interfering (si)RNA. The expression of extracellular matrix proteins in JunD deficient (JunD−/−) fibroblasts was analysed by real-time PCR and hydroxyproline assays. The mouse model of bleomycin-induced dermal fibrosis was used to assess the role of JunD in experimental fibrosis.

Results JunD was overexpressed in SSc skin and in cultured fibroblasts in a TGFβ dependent manner. The expression of JunD colocalised with pSmad 3 in fibrotic skin and silencing of Smad 3 or Smad 4 by siRNA prevented the induction of JunD by TGFβ. JunD−/− fibroblasts were less responsive to TGFβ and released less collagen upon stimulation with TGFβ. Moreover, JunD−/− mice were protected from bleomycin-induced fibrosis with reduced dermal thickening, decreased myofibroblast counts and lower collagen content of lesional skin.

Conclusions These data demonstrate that JunD is overexpressed in SSc and that JunD is a mediator of the profibrotic effects of TGFβ. Considering that inhibitors of AP-1 signalling have recently been developed and are available for clinical trials in SSc, these findings may have translational implications.

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Footnotes

  • KP and PZ contributed equally to this work.

  • Funding Grant A40 of the Interdisciplinary Center of Clinical Research (IZKF) in Erlangen, grants from the Deutsche Forschungsgesellschaft, CMH Research Projects No 00000023728 and the Career Support Award of Medicine of the Ernst Jung Foundation (to JHWD).

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the University of Erlangen-Nuremberg.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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