title: Blockade of canonical Wnt signalling ameliorates experimental dermal fibrosis.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Beyer
authors.forename: Helena
authors.initials: H
authors.lastname: Reichert
authors.forename: Hümeyra
authors.initials: H
authors.lastname: Akan
authors.forename: Tatjana
authors.initials: T
authors.lastname: Mallano
authors.forename: Amelie
authors.initials: A
authors.lastname: Schramm
authors.forename: Clara
authors.initials: C
authors.lastname: Dees
authors.forename: Katrin
authors.initials: K
authors.lastname: Palumbo-Zerr
authors.forename: Neng Yu
authors.initials: NY
authors.lastname: Lin
authors.forename: Alfiya
authors.initials: A
authors.lastname: Distler
authors.forename: Kolja
authors.initials: K
authors.lastname: Gelse
authors.forename: John
authors.initials: J
authors.lastname: Varga
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005355:Fibrosis; D051379:Mice; D008811:Mice, Inbred DBA; D011744:Pyrimidinones / Q000494:pharmacology / Q000627:therapeutic use*; D012595:Scleroderma, Systemic; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000473:pathology*; D012871:Skin Diseases / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D016896:Treatment Outcome; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use*; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C492448:ICG 001; C548732:PKF118-310; D011744:Pyrimidinones; D014227:Triazines
keywords: Fibroblasts; Systemic Sclerosis; Treatment