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Beyer, Christian; Schramm, Amelie; Akhmetshina, Alfiya; Dees, Clara; Kireva, Trayana; Gelse, Kolja; Sonnylal, Sonali; de Crombrugghe, Benoit; Taketo, Makoto Mark; Distler, Oliver; Schett, Georg; Distler, Jörg H W (2012). β-catenin is a central mediator of pro-fibrotic Wnt signaling in systemic sclerosis. Annals of the Rheumatic Diseases, 71(5):761-767.

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Abstract

OBJECTIVES:
Pathologic fibroblast activation drives fibrosis of the skin and internal organs in patients with systemic sclerosis (SSc). β-catenin is an integral part of adherens junctions and a central component of canonical Wnt signaling. Here, the authors addressed the role of β-catenin in fibroblasts for the development of SSc dermal fibrosis.
METHODS:
Nuclear accumulation of β-catenin in fibroblasts was assessed by triple staining for β-catenin, prolyl-4-hydroxylase-β and 4',6-diamidino-2-phenylindole (DAPI). The expression of Wnt proteins in the skin was analysed by real-time PCR and immunohistochemistry. Mice with fibroblast-specific stabilisation or fibroblast-specific depletion were used to evaluate the role of β-catenin in fibrosis.
RESULTS:
The auhors found significantly increased nuclear levels of β-catenin in fibroblasts in SSc skin compared to fibroblasts in the skin of healthy individuals. The accumulation of β-catenin resulted from increased expression of Wnt-1 and Wnt-10b in SSc. The authors further showed that the nuclear accumulation of β-catenin has direct implications for the development of fibrosis: Mice with fibroblast-specific stabilisation of β-catenin rapidly developed fibrosis within 2 weeks with dermal thickening, accumulation of collagen and differentiation of resting fibroblasts into myofibroblasts. By contrast, fibroblast-specific deletion of β-catenin significantly reduced bleomycin-induced dermal fibrosis.
CONCLUSIONS:
The present study findings identify β-catenin as a key player of fibroblast activation and tissue fibrosis in SSc. Although further translational studies are necessary to test the efficacy and tolerability of β-catenin/Wnt inhibition in SSc, the present findings may have clinical implications, because selective inhibitors of β-catenin/Wnt signaling have recently entered clinical trials.

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine
DDC:610 Medicine & health
Language:English
Date:2012
Deposited On:11 Jul 2012 07:16
Last Modified:27 Nov 2013 19:47
Publisher:BMJ Publishing Group
ISSN:0003-4967
Publisher DOI:10.1136/annrheumdis-2011-200568
PubMed ID:22328737
Citations:Web of Science®. Times Cited: 25
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Scopus®. Citation Count: 30

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