Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis

Alfiya Akhmetshina, Katrin Palumbo, Clara Dees, Christina Bergmann, Paulius Venalis, Pawel Zerr, Angelika Horn, Trayana Kireva, Christian Beyer, Jochen Zwerina, Holm Schneider, Anika Sadowski, Marc-Oliver Riener, Ormond A. MacDougald, Oliver Distler, Georg Schett and Jörg H.W. Distler ()
Additional contact information
Alfiya Akhmetshina: University of Erlangen-Nuremberg
Katrin Palumbo: University of Erlangen-Nuremberg
Clara Dees: University of Erlangen-Nuremberg
Christina Bergmann: University of Erlangen-Nuremberg
Paulius Venalis: University of Erlangen-Nuremberg
Pawel Zerr: University of Erlangen-Nuremberg
Angelika Horn: University of Erlangen-Nuremberg
Trayana Kireva: University of Erlangen-Nuremberg
Christian Beyer: University of Erlangen-Nuremberg
Jochen Zwerina: University of Erlangen-Nuremberg
Holm Schneider: University of Erlangen-Nuremberg
Anika Sadowski: University of Erlangen-Nuremberg
Marc-Oliver Riener: University of Erlangen-Nuremberg
Ormond A. MacDougald: University of Michigan
Oliver Distler: Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich
Georg Schett: University of Erlangen-Nuremberg
Jörg H.W. Distler: University of Erlangen-Nuremberg

Nature Communications, 2012, vol. 3, issue 1, 1-12

Abstract: Abstract The transforming growth factor-β (TGF-β) signalling pathway is a key mediator of fibroblast activation that drives the aberrant synthesis of extracellular matrix in fibrotic diseases. Here we demonstrate a novel link between transforming growth factor-β and the canonical Wnt pathway. TGF-β stimulates canonical Wnt signalling in a p38-dependent manner by decreasing the expression of the Wnt antagonist Dickkopf-1. Tissue samples from human fibrotic diseases show enhanced expression of Wnt proteins and decreased expression of Dickkopf-1. Activation of the canonical Wnt pathway stimulates fibroblasts in vitro and induces fibrosis in vivo. Transgenic overexpression of Dickkopf-1 ameliorates skin fibrosis induced by constitutively active TGF-β receptor type I signalling and also prevents fibrosis in other TGF-β-dependent animal models. These findings demonstrate that canonical Wnt signalling is necessary for TGF-β-mediated fibrosis and highlight a key role for the interaction of both pathways in the pathogenesis of fibrotic diseases.

Date: 2012
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DOI: 10.1038/ncomms1734

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