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Inhibition of hedgehog signalling prevents experimental fibrosis and induces regression of established fibrosis

Horn, Angelika and Trayana, Kireva and Palumbo-Zerr, Katrin and Dees, Clara and Tomcik, Michal and Cordazzo, Cinzia and Zerr, Pawel and Akhmetshina, Alfiya and Ruat, Martial and Distler, Oliver and Beyer, Christian and Schett, Georg and Distler, Jörg HW (2012) Inhibition of hedgehog signalling prevents experimental fibrosis and induces regression of established fibrosis. Annals of the Rheumatic Diseases, 71 (5). pp. 785-789. ISSN 0003-4967

Abstract

Objectives Tissue fi brosis is a leading cause of death
in patients with systemic sclerosis (SSc). Effective
antifi brotic treatments are not available. Here, the
authors investigated inhibition of hedgehog signalling
by targeting Smoothened (Smo) as a novel antifi brotic
approach.
Methods The activation status of the hedgehog
pathway was assessed by immunohistochemistry for Gli
transcription factors and by quantifi cation of hedgehog
target genes. Hedgehog signalling was inhibited by the
selective inhibitor LDE223 and by small interfering RNA
against Smo in the models of bleomycin-induced dermal
fi brosis and in tight-skin-1 mice.
Results Hedgehog signalling is activated in SSc and in
murine models of SSc. Inhibition of Smo either by LDE223
or by small interfering RNA prevented dermal thickening,
myofi broblast differentiation and accumulation of collagen
upon challenge with bleomycin. Targeting Smo also
exerted potent antifi brotic effects in tight-skin-1 mice and
did prevent progression of fi brosis and induced regression
of pre-established fi brosis.
Conclusions Inhibition of hedgehog signalling exerted
potent antifi brotic effects in preclinical models of SSc in
both preventive and therapeutic settings. These fi ndings
might have direct translational implications because
inhibitors of Smo are already available and yielded
promising results in initial clinical trials.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/4558

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