Inactivation of tankyrases reduces experimental fibrosis by inhibiting canonical Wnt signalling.

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.

• Authors: Alfiya Distler, Lisa Deloch, Jingang Huang, Clara Dees, Neng-Yu Lin, Katrin Palumbo-Zerr, Christian Beyer, Alexander Weidemann, Oliver Distler, Georg Schett, Jörg H W Distler
• Journal: Annals of the rheumatic diseases (Ann Rheum Dis) Vol. 72 Issue 9 Pg. 1575-80 (Sep 01 2013) ISSN: 1468-2060 [Electronic] England
• PMID: 23148305 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Heterocyclic Compounds, 3-Ring
• RNA, Small Interfering
• XAV939
• Collagen
• Tankyrases

Topics

• Animals
• Cell Differentiation (drug effects)
• Collagen (metabolism)
• Disease Models, Animal
• Fibroblasts (drug effects, enzymology, pathology)
• Fibrosis (drug therapy, enzymology, pathology)
• Gene Expression Regulation, Enzymologic (drug effects)
• Gene Knockdown Techniques
• Gene Silencing
• Genes, myc (drug effects)
• Heterocyclic Compounds, 3-Ring (pharmacology)
• Mice
• Molecular Targeted Therapy
• Myofibroblasts (drug effects, metabolism, pathology)
• RNA, Small Interfering (pharmacology)
• Scleroderma, Systemic (drug therapy, enzymology)
• Skin Diseases (drug therapy, enzymology, pathology)
• Tankyrases (antagonists & inhibitors, genetics)
• Wnt Signaling Pathway (drug effects, genetics)