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Inhibition of glycogen synthase kinase 3β induces dermal fibrosis by activation of the canonical Wnt pathway
  1. Christina Bergmann1,
  2. Alfiya Akhmetshina1,
  3. Clara Dees1,
  4. Katrin Palumbo1,
  5. Pawel Zerr1,
  6. Christian Beyer1,
  7. Jochen Zwerina1,
  8. Oliver Distler2,
  9. Georg Schett1,
  10. Jörg H W Distler1
  1. 1Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland
  1. Correspondence to Jörg H W Distler, Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Germany; joerg.distler{at}uk-erlangen.de

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.

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.

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Footnotes

  • Funding This study was supported by grant A40 of the Interdisciplinary Center of Clinical Research (IZKF) in Erlangen, Deutsche Forschungsgesellschaft and the Career Support Award of Medicine of the Ernst Jung Foundation.

  • Competing interests None.

  • Ethics approval All patients and controls signed an informed consent form approved by the local institutional review boards.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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