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Blockade of canonical Wnt signalling ameliorates experimental dermal fibrosis
  1. Christian Beyer1,
  2. Helena Reichert1,
  3. Hümeyra Akan1,
  4. Tatjana Mallano1,
  5. Amelie Schramm1,
  6. Clara Dees1,
  7. Katrin Palumbo-Zerr1,
  8. Neng Yu Lin1,
  9. Alfiya Distler1,
  10. Kolja Gelse2,
  11. John Varga3,
  12. Oliver Distler4,
  13. Georg Schett1,
  14. Jörg H W Distler1
  1. 1Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Department of Orthopaedic Trauma Surgery, University Hospital Erlangen, Erlangen, Germany
  3. 3Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  4. 4Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
  1. Correspondence to Dr Jörg H W Distler, Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Ulmenweg 18, Erlangen 91054, Germany; joerg.distler{at}uk-erlangen.de

Abstract

Background and objectives Fibrosis is a major socioeconomic burden, but effective antifibrotic therapies are not available in the clinical routine. There is growing evidence for a central role of Wnt signalling in fibrotic diseases such as systemic sclerosis, and we therefore evaluated the translational potential of pharmacological Wnt inhibition in experimental dermal fibrosis.

Methods We examined the antifibrotic effects of PKF118-310 and ICG-001, two novel inhibitors of downstream canonical Wnt signalling, in the models of prevention and treatment of bleomycin-induced dermal fibrosis as well as in experimental dermal fibrosis induced by adenoviral overexpression of a constitutively active transforming growth factor (TGF)-β receptor I.

Results PKF118-310 and ICG-001 were well tolerated throughout all experiments. Both therapeutic approaches showed antifibrotic effects in preventing and reversing bleomycin-induced dermal fibrosis as measured by skin thickness, hydroxyproline content and myofibroblast counts. PKF118-310 and ICG-001 were effective in inhibiting TGF-β receptor I-driven fibrosis as assessed by the same outcome measures.

Conclusions Blockade of canonical Wnt signalling by PKF118-310 and ICG-001 showed antifibrotic effects in different models of skin fibrosis. Both therapies were well tolerated. Although further experimental evidence for efficacy and tolerability is necessary, inhibition of canonical Wnt signalling is a promising treatment approach for fibrosis.

  • Fibroblasts
  • Systemic Sclerosis
  • Treatment

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