Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis
Top Cited Papers
Open Access
- 1 January 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 3 (1), 735
- https://doi.org/10.1038/ncomms1734
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.Keywords
This publication has 62 references indexed in Scilit:
- Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: A novel mouse model for scleroderma?Arthritis & Rheumatism, 2011
- Platelet-derived serotonin links vascular disease and tissue fibrosisThe Journal of Experimental Medicine, 2011
- Exogenously administered secreted frizzled related protein 2 (Sfrp2) reduces fibrosis and improves cardiac function in a rat model of myocardial infarctionProceedings of the National Academy of Sciences of the United States of America, 2010
- Inhibition of Wnt/β-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosisProceedings of the National Academy of Sciences of the United States of America, 2010
- Wnt/β-Catenin Signaling: Components, Mechanisms, and DiseasesDevelopmental Cell, 2009
- Targeted Disruption of the Wnt Regulator Kremen Induces Limb Defects and High Bone DensityMolecular and Cellular Biology, 2008
- DKK1 Antagonizes Wnt Signaling without Promotion of LRP6 Internalization and DegradationOnline Journal of Public Health Informatics, 2008
- R-Spondin Family Members Regulate the Wnt Pathway by a Common MechanismMolecular Biology of the Cell, 2008
- Wnt/β-catenin signaling: new (and old) players and new insightsCurrent Opinion in Cell Biology, 2008
- Cellular and molecular mechanisms of fibrosisThe Journal of Pathology, 2007