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Inhibition of hedgehog signalling prevents experimental fibrosis and induces regression of established fibrosis
  1. Angelika Horn1,
  2. Trayana Kireva1,
  3. Katrin Palumbo-Zerr1,
  4. Clara Dees1,
  5. Michal Tomcik1,2,
  6. Cinzia Cordazzo1,3,
  7. Pawel Zerr1,
  8. Alfiya Akhmetshina1,
  9. Martial Ruat4,
  10. Oliver Distler5,
  11. Christian Beyer1,
  12. Georg Schett1,
  13. Jörg H W Distler1
  1. 1Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Institute of Rheumatology and Connective Tissue Research Laboratory, Department of Rheumatology of the First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
  3. 3Laboratory of Respiratory Cell Biology, Dipartimento Cardiotoracico e Vascolare, University of Pisa, Pisa, Italy
  4. 4CNRS, UPR3294, Laboratoire de Neurobiologie et Developpement, Institut de Neurobiologie Alfred Fessard, Gif-sur-Yvette, France
  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, University of Erlangen-Nuremberg, Erlangen 91054, Germany; joerg.distler{at}


Objectives Tissue fibrosis is a leading cause of death in patients with systemic sclerosis (SSc). Effective antifibrotic treatments are not available. Here, the authors investigated inhibition of hedgehog signalling by targeting Smoothened (Smo) as a novel antifibrotic approach.

Methods The activation status of the hedgehog pathway was assessed by immunohistochemistry for Gli transcription factors and by quantification of hedgehog target genes. Hedgehog signalling was inhibited by the selective inhibitor LDE223 and by small interfering RNA against Smo in the models of bleomycin-induced dermal fibrosis and in tight-skin-1 mice.

Results Hedgehog signalling is activated in SSc and in murine models of SSc. Inhibition of Smo either by LDE223 or by small interfering RNA prevented dermal thickening, myofibroblast differentiation and accumulation of collagen upon challenge with bleomycin. Targeting Smo also exerted potent antifibrotic effects in tight-skin-1 mice and did prevent progression of fibrosis and induced regression of pre-established fibrosis.

Conclusions Inhibition of hedgehog signalling exerted potent antifibrotic effects in preclinical models of SSc in both preventive and therapeutic settings. These findings might have direct translational implications because inhibitors of Smo are already available and yielded promising results in initial clinical trials.

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  • Contributors AH and JHWD designed the study. AH, TK, KP, CD, MT, CC, PZ, CB, AA and MR acquired data. AH, TK, MR, OD, CB, GS and JHWD interpreted the data. AH, CB, OD, GS and JHWD prepared the manuscript.

  • Competing interests None.

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