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

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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.
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.
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.
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.


37 citations in Web of Science®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine
Dewey Decimal Classification:610 Medicine & health
Deposited On:12 Jul 2012 05:58
Last Modified:05 Apr 2016 15:52
Publisher:BMJ Publishing Group
Publisher DOI:10.1136/annrheumdis-2011-200883
PubMed ID:22402139

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