title: Inactivation of evenness interrupted (EVI) reduces experimental fibrosis by combined inhibition of canonical and non-canonical Wnt signalling.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, , Erlangen, Germany.
authors.forename: Alfiya
authors.initials: A
authors.lastname: Distler
authors.forename: Clara
authors.initials: C
authors.lastname: Ziemer
authors.forename: Christian
authors.initials: C
authors.lastname: Beyer
authors.forename: Neng-Yu
authors.initials: NY
authors.lastname: Lin
authors.forename: Chih-Wei
authors.initials: CW
authors.lastname: Chen
authors.forename: Katrin
authors.initials: K
authors.lastname: Palumbo-Zerr
authors.forename: Clara
authors.initials: C
authors.lastname: Dees
authors.forename: Alexander
authors.initials: A
authors.lastname: Weidemann
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; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis; D055785:Gene Knockdown Techniques; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000502:physiology; D012595:Scleroderma, Systemic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012867:Skin / Q000473:pathology*; D060449:Wnt Signaling Pathway / Q000235:genetics* / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; C549111:WLS protein, human; D051176:beta Catenin; D048670:MAP Kinase Kinase 4
keywords: Fibroblasts; Systemic Sclerosis; Treatment