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Inactivation of tankyrases reduces experimental fibrosis by inhibiting canonical Wnt signalling
  1. Alfiya Distler1,
  2. Lisa Deloch1,
  3. Jingang Huang1,
  4. Clara Dees1,
  5. Neng-Yu Lin1,
  6. Katrin Palumbo-Zerr1,
  7. Christian Beyer1,
  8. Alexander Weidemann2,
  9. Oliver Distler3,
  10. Georg Schett1,
  11. Jörg H W Distler1
  1. 1Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Department of Internal Medicine 4, Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen, Germany
  3. 3Department of Rheumatology and Center of Experimental Rheumatology, University Hospital Zurich, Zurich Center of Integrative Human Physiology (ZIHP), Zurich, Switzerland
  1. Correspondence to Dr Jörg H W Distler, Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Ulmenweg 18, Erlangen 91054, Germany; joerg.distler{at}uk-erlangen.de

Abstract

Objectives 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.

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