Alfiya Akhmetshina 1 , Katrin Palumbo 1 , Clara Dees 1 , Christina Bergmann 1 , Paulius Venalis 1 , Pawel Zerr 1 , Angelika Horn 1 , Trayana Kireva 1 , Christian Beyer 1 , Jochen Zwerina 1 , Holm Schneider 2 , Anika Sadowski 2 , Marc-Oliver Riener 3 , Ormond A. MacDougald 4 , Oliver Distler 5 , Georg Schett 1 , Jörg H.W. Distler a , 1
13 March 2012
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.
Aberrant activation of the TGF-β pathway leads to fibrotic disease. Distler and colleagues show that TGF-β-mediated fibrosis requires the decrease of Dickkopf-1, an antagonist of canonical Wnt signalling, suggesting that the two pathways interact for the manifestation of this disease.