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

Language
en
Document Type
Article
Issue Date
2016-11-15
Issue Year
2012
Authors
Horn, Angelika
Kireva, Trayana
Palumbo-Zerr, Katrin
Dees, Clara
Tomcik, Michal
Cordazzo, Cinzia
Zerr, Pawel
Akhmetshina, Alfiya
Ruat, Martial
Distler, Oliver
Editor
Abstract

Objectives: Tissue fibrosis is a leading cause of death in patients with systemic sclerosis (SSc). Effective antifibrotic treatments are not available. Here, the authors investigated inhibition of hedgehog signalling by targeting Smoothened (Smo) as a novel antifibrotic approach.

Methods: The activation status of the hedgehog pathway was assessed by immunohistochemistry for Gli transcription factors and by quantification 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 fibrosis 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, myofibroblast differentiation and accumulation of collagen upon challenge with bleomycin. Targeting Smo also exerted potent antifibrotic effects in tight-skin-1 mice and did prevent progression of fibrosis and induced regression of pre-established fibrosis.

Conclusions: Inhibition of hedgehog signalling exerted potent antifibrotic effects in preclinical models of SSc in both preventive and therapeutic settings. These findings might have direct translational implications because inhibitors of Smo are already available and yielded promising results in initial clinical trials.

Journal Title
Annals of the Rheumatic Diseases
Volume
71
Issue
5
Citation

Annals of the Rheumatic Diseases 71.5 (2012): S. 785-789. http://ard.bmj.com/content/71/5/785

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