Article Text

other Versions

PDF
Extended report
β-catenin is a central mediator of pro-fibrotic Wnt signaling in systemic sclerosis
  1. Christian Beyer1,
  2. Amelie Schramm1,
  3. Alfiya Akhmetshina1,
  4. Clara Dees1,
  5. Trayana Kireva1,
  6. Kolja Gelse2,
  7. Sonali Sonnylal3,
  8. Benoit de Crombrugghe3,
  9. Makoto Mark Taketo4,
  10. Oliver Distler5,
  11. Georg Schett1,
  12. Jörg H W Distler1
  1. 1Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Department of Surgery, Division of Trauma Surgery and Orthopaedic Surgery, University of Erlangen-Nuremberg, Erlangen, Germany
  3. 3Department of Genetics, University of Texas, M D Anderson Cancer Center, Houston, Texas, USA
  4. 4Department of Pharmacology, Graduate School of Medicine, Kyoto University Yoshida-Konoé-cho, Sakyo, Kyoto, Japan
  5. 5Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
  1. Correspondence to Jörg H W Distler, Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Krankenhausstr 12, 91054 Erlangen, Germany; joerg.distler{at}uk-erlangen.de

Abstract

Objectives Pathologic fibroblast activation drives fibrosis of the skin and internal organs in patients with systemic sclerosis (SSc). β-catenin is an integral part of adherens junctions and a central component of canonical Wnt signaling. Here, the authors addressed the role of β-catenin in fibroblasts for the development of SSc dermal fibrosis.

Methods Nuclear accumulation of β-catenin in fibroblasts was assessed by triple staining for β-catenin, prolyl-4-hydroxylase-β and 4′,6-diamidino-2-phenylindole (DAPI). The expression of Wnt proteins in the skin was analysed by real-time PCR and immunohistochemistry. Mice with fibroblast-specific stabilisation or fibroblast-specific depletion were used to evaluate the role of β-catenin in fibrosis.

Results The auhors found significantly increased nuclear levels of β-catenin in fibroblasts in SSc skin compared to fibroblasts in the skin of healthy individuals. The accumulation of β-catenin resulted from increased expression of Wnt-1 and Wnt-10b in SSc. The authors further showed that the nuclear accumulation of β-catenin has direct implications for the development of fibrosis: Mice with fibroblast-specific stabilisation of β-catenin rapidly developed fibrosis within 2 weeks with dermal thickening, accumulation of collagen and differentiation of resting fibroblasts into myofibroblasts. By contrast, fibroblast-specific deletion of β-catenin significantly reduced bleomycin-induced dermal fibrosis.

Conclusions The present study findings identify β-catenin as a key player of fibroblast activation and tissue fibrosis in SSc. Although further translational studies are necessary to test the efficacy and tolerability of β-catenin/Wnt inhibition in SSc, the present findings may have clinical implications, because selective inhibitors of β-catenin/Wnt signaling have recently entered clinical trials.

Statistics from Altmetric.com

Footnotes

  • Funding Christian Beyer: Research scholar at the Interdisciplinary Center of Clinical Research (IZKF) in Erlangen; Grant from the Erlanger Leistungsbezogene Anschubfinanzierung und Nachwuchsförderung (ELAN). Jörg Distler: Grant A40 of the Interdisciplinary Center of Clinical Research (IZKF) in Erlangen; grants from the Deutsche Forschungsgesellschaft; and the Career Support Award of Medicine of the Ernst Jung Foundation.

  • Competing interests None.

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

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.