S100A4 amplifies TGF-β-induced fibroblast activation in systemic sclerosis

肌成纤维细胞 纤维化 SMAD公司 转化生长因子 医学 成纤维细胞 基因敲除 免疫印迹 癌症研究 病理 内分泌学 生物 细胞培养 遗传学 生物化学 基因
作者
Michal Tomčík,Katrin Palumbo‐Zerr,Pawel Zerr,Jérôme Avouac,Clara Dees,Barbora Šumová,Alfiya Distler,Christian Beyer,L. Andres Cerezo,Radim Bečvář,Oliver Distler,Mariam Grigorian,Georg Schett,Ladislav Šenolt,Jörg H. W. Distler
出处
期刊:Annals of the Rheumatic Diseases [BMJ]
卷期号:74 (9): 1748-1755 被引量:58
标识
DOI:10.1136/annrheumdis-2013-204516
摘要

Objectives

S100A4 is a calcium binding protein with regulatory functions in cell homeostasis, proliferation and differentiation that has been shown to promote cancer progression and metastasis. In the present study, we evaluated the role of S100A4 in fibroblast activation in systemic sclerosis (SSc).

Methods

The expression of S100A4 was analysed in human samples, murine models of SSc and in cultured fibroblasts by real-time PCR, immunohistochemistry and western blot. The functional role of S100A4 was evaluated using siRNA, overexpression, recombinant protein and S100A4 knockout (S100A4−/−) mice. Transforming growth factor β (TGF-β) signalling was assessed by reporter assays, staining for phosphorylated Smad2/3 and analyses of target genes.

Results

The expression of S100A4 was increased in SSc skin and in experimental fibrosis in a TGF-β/Smad-dependent manner. Overexpression of S100A4 or stimulation with recombinant S100A4 induced an activated phenotype in resting normal fibroblasts. In contrast, knockdown of S100A4 reduced the pro-fibrotic effects of TGF-β and decreased the release of collagen. S100A4−/− mice were protected from bleomycin-induced skin fibrosis with reduced dermal thickening, decreased hydroxyproline content and lower myofibroblast counts. Deficiency of S100A4 also ameliorated fibrosis in the tight-skin-1 (Tsk-1) mouse model.

Conclusions

We characterised S100A4 as a downstream mediator of the stimulatory effects of TGF-β on fibroblasts in SSc. TGF-β induces the expression of S100A4 to stimulate the release of collagen in SSc fibroblasts and induce fibrosis. Since S100A4 is essentially required for the pro-fibrotic effects of TGF-β and neutralising antibodies against S100A4 are currently evaluated, S100A4 might be a candidate for novel antifibrotic therapies.
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