Inactivation of tankyrases reduces experimental fibrosis by inhibiting canonical Wnt signalling

Language
en
Document Type
Article
Issue Date
2016-11-15
Issue Year
2013
Authors
Distler, Alfiya
Deloch, Lisa
Huang, Jingang
Dees, Clara
Lin, Neng-Yu
Palumbo-Zerr, Katrin
Beyer, Christian
Weidemann, Alexander
Distler, Oliver
Schett, Georg
Editor
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.

Journal Title
Annals of the Rheumatic Diseases
Volume
72
Issue
9
Citation
Annals of the Rheumatic Diseases 72.9 (2013): S. 1575-1580. <http://ard.bmj.com/content/72/9/1575>
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