title: Inhibition of glycogen synthase kinase 3β induces dermal fibrosis by activation of the canonical Wnt pathway.
abstract: OBJECTIVE
  Glycogen synthase kinase 3β (GSK-3) regulates the phosphorylation and subsequent degradation of β-catenin, thereby preventing aberrant activation of the canonical Wnt pathway. A study was undertaken to define the role of GSK-3 in fibroblast activation and in experimental models of systemic sclerosis (SSc).
  
  
  METHODS
  siRNA and specific inhibitors were used to inhibit GSK-3 in cultured fibroblasts and in mice. Activation of the canonical Wnt signalling was analysed by determining the levels of nuclear β-catenin and by measuring the mRNA levels of the Wnt target gene Axin2. The effects of GSK-3 on the release of collagen were evaluated in human dermal fibroblasts and in the mouse model of bleomycin-induced skin fibrosis in tight-skin-1 (tsk-1) mice.
  
  
  RESULTS
  Targeting GSK-3 potently activated the canonical Wnt pathway in fibroblasts in vitro and in vivo. Inactivation of GSK-3 dose-dependently stimulated the release of collagen from cultured fibroblasts in a β-catenin-dependent manner and further resulted in progressive accumulation of collagen and dermal thickening in mice. Inhibition of GSK-3 aggravated experimental fibrosis in bleomycin-challenged mice and in tsk-1 mice.
  
  
  CONCLUSIONS
  Inhibition of GSK-3 activates the canonical Wnt pathway in fibroblasts, stimulates the release of collagen from fibroblasts, exacerbates experimental fibrosis and is sufficient to induce fibrosis. GSK-3 is therefore a key regulator of the canonical Wnt signalling in fibroblasts and inhibition of GSK-3 results in fibroblast activation and increased release of collagen.
authors.affiliation: Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Bergmann
authors.forename: Alfiya
authors.initials: A
authors.lastname: Akhmetshina
authors.forename: Clara
authors.initials: C
authors.lastname: Dees
authors.forename: Katrin
authors.initials: K
authors.lastname: Palumbo
authors.forename: Pawel
authors.initials: P
authors.lastname: Zerr
authors.forename: Christian
authors.initials: C
authors.lastname: Beyer
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
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; D001761:Bleomycin; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D055785:Gene Knockdown Techniques / Q000379:methods; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D008811:Mice, Inbred DBA; D034741:RNA, Small Interfering / Q000235:genetics; D012595:Scleroderma, Systemic / Q000201:enzymology* / Q000378:metabolism; D012867:Skin / Q000473:pathology*; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D034741:RNA, Small Interfering; C417521:SB 216763; D001761:Bleomycin; D003094:Collagen; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3