期刊
ANNALS OF THE RHEUMATIC DISEASES
卷 73, 期 3, 页码 624-627出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/annrheumdis-2013-203995
关键词
Fibroblasts; Systemic Sclerosis; Treatment
类别
资金
- 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, WE4275/3-1]
- IZKF in Erlangen [A40]
- ELAN-Program of the University of Erlangen-Nuremberg
- Career Support Award of Medicine of the Ernst Jung Foundation
Objectives Canonical as well as non-canonical Wnt signalling pathways have emerged as core pathways of fibrosis. Their profibrotic effects are mediated via distinct intracellular cascades independently of each other. Thus, inhibition of both pathways may have additive antifibrotic effects. Here, we knocked down evenness interrupted (EVI) to simultaneously target for the first time canonical and non-canonical Wnt signalling in experimental fibrosis. Methods The antifibrotic effects of siRNA-mediated knockdown of EVI were evaluated in the mouse models of bleomycin-induced skin fibrosis and in fibrosis induced by adenoviral overexpression of a constitutively active TGF- receptor I (AdTBRI). Results Knockdown of EVI decreased the release of canonical and non-canonical Wnt ligands by fibroblasts and reduced the activation of canonical and non-canonical Wnt cascades in experimental fibrosis with decreased accumulation of -catenin and phosphorylated JNK and cJun. Inactivation of EVI exerted potent antifibrotic effects and reduced dermal thickening, myofibroblast differentiation and accumulation of collagen in the mouse models of bleomycin-induced and AdTBR-induced fibrosis. Conclusions Inhibition of Wnt secretion by knockdown of EVI inhibits canonical and non-canonical Wnt signalling and effectively reduces experimental fibrosis in different preclinical models. Inhibition of Wnt secretion may thus be an interesting approach for the treatment of fibrosis.
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