Inhibition of glycogen synthase kinase 3β induces dermal fibrosis by activation of the canonical Wnt pathway

Ann Rheum Dis. 2011 Dec;70(12):2191-8. doi: 10.1136/ard.2010.147140. Epub 2011 Aug 25.


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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bleomycin
  • Cells, Cultured
  • Collagen / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Female
  • Fibroblasts / metabolism
  • Fibrosis
  • Gene Knockdown Techniques / methods
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / physiology*
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Indoles / pharmacology
  • Male
  • Maleimides / pharmacology
  • Mice
  • Mice, Inbred DBA
  • RNA, Small Interfering / genetics
  • Scleroderma, Systemic / enzymology*
  • Scleroderma, Systemic / metabolism
  • Skin / pathology*
  • Wnt Signaling Pathway / drug effects
  • Wnt Signaling Pathway / physiology*


  • Enzyme Inhibitors
  • Indoles
  • Maleimides
  • RNA, Small Interfering
  • SB 216763
  • Bleomycin
  • Collagen
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3