S100A4 amplifies TGF-β-induced fibroblast activation in systemic sclerosis
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
24709861
DOI
10.1136/annrheumdis-2013-204516
PII: S0003-4967(24)02587-1
Knihovny.cz E-resources
- MeSH
- Adult MeSH
- Fibroblasts metabolism MeSH
- Skin metabolism MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Disease Models, Animal MeSH
- Mice, Knockout MeSH
- Mice MeSH
- Smad2 Protein metabolism MeSH
- Smad3 Protein metabolism MeSH
- S100 Proteins metabolism MeSH
- S100 Calcium-Binding Protein A4 MeSH
- Aged MeSH
- Scleroderma, Systemic metabolism MeSH
- Transforming Growth Factor beta metabolism MeSH
- Animals MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Mice MeSH
- Aged MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Smad2 Protein MeSH
- Smad3 Protein MeSH
- S100 Proteins MeSH
- S100 Calcium-Binding Protein A4 MeSH
- S100A4 protein, human MeSH Browser
- S100a4 protein, mouse MeSH Browser
- Transforming Growth Factor beta MeSH
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.
References provided by Crossref.org
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