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Jun N-terminal kinase as a potential molecular target for prevention and treatment of dermal fibrosis
  1. Nicole Reich1,
  2. Michal Tomcik1,2,
  3. Pawel Zerr1,
  4. Veronika Lang1,
  5. Clara Dees1,
  6. Jérome Avouac1,3,
  7. Katrin Palumbo1,
  8. Angelika Horn1,
  9. Alfiya Akhmetshina1,
  10. Christian Beyer1,
  11. Weilin Xie4,
  12. Brydon L Bennett4,
  13. Oliver Distler5,
  14. Georg Schett1,
  15. Jörg H W Distler1
  1. 1Department for Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Department of Clinical and Experimental Rheumatology, First Faculty of Medicine, Institute of Rheumatology, Charles University in Prague, Prague, Czech Republic
  3. 3Paris Descartes University, Rheumatology A department, Cochin Hospital and INSERM U781, Necker Hospital, Paris, France
  4. 4Celgene, San Diego, California, USA
  5. 5Center 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 and Institute for Clinical Immunology, Universitätsstr, University of Erlangen-Nuremberg, 91054, Erlangen, Germany; joerg.distler{at}uk-erlangen.de

Abstract

Objectives The hallmark of systemic sclerosis (SSc) is the accumulation of extracellular matrix proteins by pathologically activated fibroblasts. This study analysed the antifibrotic effects of the selective c-Jun N-terminal kinase (JNK) inhibitor, CC-930, which recently entered first clinical trials as a novel antifibrotic approach.

Methods Phosphorylated c-Jun was detected by western blot and immunohistochemistry. The model of bleomycin-induced dermal fibrosis and the tight skin 1 (TSK1) mouse model were used to investigate the effects of CC-930 on the prevention of experimental fibrosis. The potential of CC-930 to induce regression of fibrosis was assessed in a modified model of established fibrosis.

Results Transforming growth factor beta (TGFβ) and platelet-derived growth factor (PDGF) activate JNK and stimulate the phosphorylation of its downstream target c-Jun. Incubation with CC-930 prevented the phosphorylation of c-Jun and reduced the stimulatory levels of these cytokines on the release of collagen. Inhibition of JNK prevented dermal thickening, myofibroblast differentiation and the accumulation of collagen in a dose-dependent manner in mice challenged with bleomycin and in TSK1 mice. In addition to the prevention of fibrosis, treatment with pharmacologically relevant doses of CC-930 also induced regression of established experimental fibrosis.

Conclusions These data identify JNK as a downstream mediator of the pro-fibrotic effects of of TGFβ and PDGF in SSc fibroblasts. Selective inhibition of JNK by CC-930 exerted potent antifibrotic effects in vitro and in different models in vivo. JNK might thus be a novel molecular target for the treatment of fibrosis in SSc.

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Footnotes

  • Funding This study was funded by grants DI 1537/1-1 and DI 1537/2-1 of the Deutsche Forschungsgesellschaft, the Career Support Award of Medicine of the Ernst Jung Foundation, grants A20 and A40 of the Interdisciplinary Center of Clinical Research in Erlangen, a grant from Celgene and the CMH research project no 00000023728.

  • Ethics approval Ethics approval was obtained from the local institutional review boards.

  • Patient consent Obtained.

  • Competing interests None.

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

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