Wnt/β-catenin signaling is hyperactivated in systemic sclerosis and induces Smad-dependent fibrotic responses in mesenchymal cells.
Wnt/β-catenin signaling is hyperactivated in systemic sclerosis and induces Smad-dependent fibrotic responses in mesenchymal cells.
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DOI：
10.1002/art.34424
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发表时间：
2012-08
影响因子：
--
通讯作者：
Varga, John
中科院分区：
文献类型：
--
作者：
Wei, Jun;Fang, Feng;Lam, Anna P.;Sargent, Jennifer L.;Hamburg, Emily;Hinchcliff, Monique E.;Gottardi, Cara J.;Atit, Radhika;Whitfield, Michael L.;Varga, John
人类疾病和动物模型中的纤维化与Wnt/β-catenin通路异常激活有关。Wnt/β-catenin信号在系统性硬化症（SSc）中的调控、活性、作用机制和意义尚未明确。分析Wnt信号通路组分在SSc皮肤活检中的表达。在外植的人间充质细胞中检测了典型Wnt/ß-catenin对纤维化反应的调控。通过增殖、迁移和凝胶收缩实验研究纤维化反应。研究了典型Wnt信号对皮下前脂肪细胞命运的影响。对已发表的全基因组表达数据集的分析显示，在dcSSc患者亚群的皮肤活检中，Wnt受体Fzd2和Wnt靶点Lef1的表达升高，Wnt拮抗剂Dkk2和Wif1的表达降低。免疫组化显示细胞核β-连环蛋白表达增加。在体外，Wnt3a诱导ß-catenin活化，刺激成纤维细胞增殖、迁移、凝胶收缩和肌成纤维细胞分化，以及促纤维化基因表达。遗传学和药理学方法被用来证明这些促纤维化反应涉及通过Smads的自分泌TGF-β信号传导。相反，在外植的皮下前脂肪细胞中，Wnt3a抑制脂肪形成，促进肌成纤维细胞分化。在SSc皮肤活检中，典型Wnt信号被过度激活，在外植的间充质细胞中，Wnt3a刺激纤维化反应，同时抑制脂肪生成。综上所述，这些结果表明Wnt具有强大的促纤维化作用，典型性Wnt信号在SSc纤维化和脂肪萎缩的发病机制中起重要作用。
Fibrosis in human diseases and animal models is associated with aberrant Wnt/β-catenin pathway activation. The regulation, activity, mechanism of action and significance of Wnt/β-catenin signaling in the context of systemic sclerosis (SSc) has not been characterized. Expression of Wnt signaling pathway components in SSc skin biopsies was analyzed. The regulation of profibrotic responses by canonical Wnt/ß-catenin was examined in explanted human mesenchymal cells. Fibrotic responses were studied by proliferation, migration and gel contraction assays. The fate specification of subcutaneous preadipocytes by canonical Wnt signaling was evaluated. Analysis of published genome-wide expression datasets revealed elevated expression of the Wnt receptor Fzd2 and the Wnt target Lef1, and decreased expression of Wnt antagonists Dkk2 and Wif1 in skin biopsies from subsets of dcSSc patients. Immunohistochemistry showed increased nuclear β-catenin expression in these biopsies. In vitro, Wnt3a induced ß-catenin activation, stimulated fibroblast proliferation, migration, gel contraction and myofibroblast differentiation, and profibrotic gene expression. Genetic and pharmacological approaches were used to demonstrate that these profibrotic responses involved autocrine TGF-β signaling via Smads. In contrast, in explanted subcutaneous preadipocytes Wnt3a repressed adipogenesis and promoted myofibroblast differentiation. Canonical Wnt signaling was hyperactivated in SSc skin biopsies, and in explanted mesenchymal cells Wnt3a stimulated fibrogenic responses while suppressing adipogenesis. Together, these results indicate that Wnts have potent profibrotic effects and canonical Wnt signaling plays an important role in the pathogenesis of fibrosis and lipoatrophy in SSc.
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DOI：
10.1038/jid.2008.445
发表时间：
2009-07
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
Chien AJ;Conrad WH;Moon RT
通讯作者：
Moon RT
影响因子：
4.1
作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1073/pnas.102657399
发表时间：
2002-05-14
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
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