Journal
NATURE COMMUNICATIONS
Volume 3, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms1734
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Funding
- Interdisciplinary Center of Clinical Research (IZKF) in Erlangen
- Deutsche Forschungsgesellschaft [DI 1537/1-1, DI 1537/2-1, DI 1537/4-1, DI-1537/5-1, AK 144/1-1, SCHE 1583/7-1]
- IMI
- Bundesministerium fur Bildung und Forschung [01EC1002D]
- Ernst Jung Foundation
- NIH [DK51563, DK62876, DK92759]
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The transforming growth factor-beta (TGF-beta) 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-beta and the canonical Wnt pathway. TGF-beta 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-beta receptor type I signalling and also prevents fibrosis in other TGF-beta-dependent animal models. These findings demonstrate that canonical Wnt signalling is necessary for TGF-beta-mediated fibrosis and highlight a key role for the interaction of both pathways in the pathogenesis of fibrotic diseases.
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