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Inactivation of evenness interrupted (EVI) reduces experimental fibrosis by combined inhibition of canonical and non-canonical Wnt signalling
  1. Alfiya Distler1,
  2. Clara Ziemer1,
  3. Christian Beyer1,
  4. Neng-Yu Lin1,
  5. Chih-Wei Chen1,
  6. Katrin Palumbo-Zerr1,
  7. Clara Dees1,
  8. Alexander Weidemann2,
  9. Oliver Distler3,
  10. Georg Schett1,
  11. Jörg H W Distler1
  1. 1Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Department of Internal Medicine 4, University of Erlangen-Nuremberg, Erlangen, Germany
  3. 3Department of Rheumatology and Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland
  1. Correspondence to Dr Jörg H W Distler, Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Ulmenweg 18, Erlangen 91054, Germany; joerg.distler{at}uk-erlangen.de

Abstract

Objectives Canonical as well as non-canonical Wnt signalling pathways have emerged as core pathways of fibrosis. Their profibrotic effects are mediated via distinct intracellular cascades independently of each other. Thus, inhibition of both pathways may have additive antifibrotic effects. Here, we knocked down evenness interrupted (EVI) to simultaneously target for the first time canonical and non-canonical Wnt signalling in experimental fibrosis.

Methods The antifibrotic effects of siRNA-mediated knockdown of EVI were evaluated in the mouse models of bleomycin-induced skin fibrosis and in fibrosis induced by adenoviral overexpression of a constitutively active TGF-β receptor I (AdTBRI).

Results Knockdown of EVI decreased the release of canonical and non-canonical Wnt ligands by fibroblasts and reduced the activation of canonical and non-canonical Wnt cascades in experimental fibrosis with decreased accumulation of β-catenin and phosphorylated JNK and cJun. Inactivation of EVI exerted potent antifibrotic effects and reduced dermal thickening, myofibroblast differentiation and accumulation of collagen in the mouse models of bleomycin-induced and AdTBR-induced fibrosis.

Conclusions Inhibition of Wnt secretion by knockdown of EVI inhibits canonical and non-canonical Wnt signalling and effectively reduces experimental fibrosis in different preclinical models. Inhibition of Wnt secretion may thus be an interesting approach for the treatment of fibrosis.

  • Fibroblasts
  • Systemic Sclerosis
  • Treatment

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