title: Inactivation of tankyrases reduces experimental fibrosis by inhibiting canonical Wnt signalling.
abstract: OBJECTIVE
  Canonical Wnt signalling has recently emerged as a key mediator of fibroblast activation and tissue fibrosis in systemic sclerosis. Here, we investigated tankyrases as novel molecular targets for inhibition of canonical Wnt signalling in fibrotic diseases.
  
  
  METHODS
  The antifibrotic effects of the tankyrase inhibitor XAV-939 or of siRNA-mediated knockdown of tankyrases were evaluated in the mouse models of bleomycin-induced dermal fibrosis and in experimental fibrosis induced by adenoviral overexpression of a constitutively active TGF-β receptor I (Ad-TBRI).
  
  
  RESULTS
  Inactivation of tankyrases prevented the activation of canonical Wnt signalling in experimental fibrosis and reduced the nuclear accumulation of β-catenin and the mRNA levels of the target gene c-myc. Treatment with XAV-939 or siRNA-mediated knockdown of tankyrases in the skin effectively reduced bleomycin-induced dermal thickening, differentiation of resting fibroblasts into myofibroblasts and accumulation of collagen. Potent antifibrotic effects were also observed in Ad-TBRI driven skin fibrosis. Inhibition of tankyrases was not limited by local or systemic toxicity.
  
  
  CONCLUSIONS
  Inactivation of tankyrases effectively abrogated the activation of canonical Wnt signalling and demonstrated potent antifibrotic effects in well-tolerated doses. Thus, tankyrases might be candidates for targeted therapies in fibrotic diseases.
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: Lisa
authors.initials: L
authors.lastname: Deloch
authors.forename: Jingang
authors.initials: J
authors.lastname: Huang
authors.forename: Clara
authors.initials: C
authors.lastname: Dees
authors.forename: Neng-Yu
authors.initials: NY
authors.lastname: Lin
authors.forename: Katrin
authors.initials: K
authors.lastname: Palumbo-Zerr
authors.forename: Christian
authors.initials: C
authors.lastname: Beyer
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; D002454:Cell Differentiation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005355:Fibrosis / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D016259:Genes, myc / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D051379:Mice; D058990:Molecular Targeted Therapy; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D012595:Scleroderma, Systemic / Q000188:drug therapy / Q000201:enzymology; D012871:Skin Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D038501:Tankyrases / Q000037:antagonists & inhibitors* / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000235:genetics
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D034741:RNA, Small Interfering; C544261:XAV939; D003094:Collagen; D038501:Tankyrases