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

The transforming growth factor-ß (TGF-ß) 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-ß and the canonical Wnt pathway. TGF-ß 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-ß receptor type I signalling and also prevents fibrosis in other TGF-ß-dependent animal models. These findings demonstrate that canonical Wnt signalling is necessary for TGF-ß-mediated fibrosis and highlight a key role for the interaction of both pathways in the pathogenesis of fibrotic diseases.