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

被引：735

作者：

Akhmetshina, Alfiya ^{[1
,2
]}

Palumbo, Katrin ^{[1
,2
]}

Dees, Clara ^{[1
,2
]}

Bergmann, Christina ^{[1
,2
]}

Venalis, Paulius ^{[1
,2
]}

Zerr, Pawel ^{[1
,2
]}

Horn, Angelika ^{[1
,2
]}

Kireva, Trayana ^{[1
,2
]}

Beyer, Christian ^{[1
,2
]}

Zwerina, Jochen ^{[1
,2
]}

Schneider, Holm ^{[3
]}

Sadowski, Anika ^{[3
]}

Riener, Marc-Oliver ^{[4
]}

MacDougald, Ormond A. ^{[5
]}

Distler, Oliver ^{[6
,7
]}

Schett, Georg ^{[1
,2
]}

Distler, Joerg H. W. ^{[1
,2
]}

机构：

[1] Univ Erlangen Nurnberg, Dept Internal Med 3, D-91054 Erlangen, Germany

[2] Univ Erlangen Nurnberg, Inst Clin Immunol, D-91054 Erlangen, Germany

[3] Univ Erlangen Nurnberg, Dept Pediat, D-91054 Erlangen, Germany

[4] Univ Erlangen Nurnberg, Dept Pathol, D-91054 Erlangen, Germany

[5] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48105 USA

[6] Univ Zurich Hosp, Ctr Expt Rheumatol, CH-8091 Zurich, Switzerland

[7] Univ Zurich Hosp, Zurich Ctr Integrat Human Physiol, CH-8091 Zurich, Switzerland

来源：

NATURE COMMUNICATIONS | 2012年 / 3卷

关键词：

GROWTH-FACTOR-BETA; SYSTEMIC-SCLEROSIS; EXTRACELLULAR-MATRIX; MECHANISMS; DICKKOPF-1; PATHWAY; FIBROBLASTS; INHIBITION; EXPRESSION; PROTEINS;

D O I：

10.1038/ncomms1734

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页数：12

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