The transcription factor GLI2 as a downstream mediator of transforming growth factor-β-induced fibroblast activation in SSc
Language English Country United States Media print-electronic
Document type Journal Article
PubMed
27793816
DOI
10.1136/annrheumdis-2016-209698
PII: S0003-4967(24)02823-1
Knihovny.cz E-resources
- Keywords
- Fibroblasts, Systemic Sclerosis, Treatment,
- MeSH
- Anilides pharmacology MeSH
- Adult MeSH
- Fibroblasts drug effects metabolism MeSH
- Fibrosis MeSH
- Gene Knockout Techniques MeSH
- Plasminogen Activator Inhibitor 1 genetics MeSH
- Collagen Type I genetics MeSH
- Cells, Cultured MeSH
- Skin drug effects pathology MeSH
- Middle Aged MeSH
- Humans MeSH
- RNA, Messenger metabolism MeSH
- Young Adult MeSH
- Mice, Knockout MeSH
- Mice, Transgenic MeSH
- Mice MeSH
- Pulmonary Fibrosis chemically induced metabolism MeSH
- Zinc Finger Protein Gli2 MeSH
- Smad3 Protein metabolism MeSH
- Protein Serine-Threonine Kinases antagonists & inhibitors genetics MeSH
- Hedgehog Proteins metabolism MeSH
- Pteridines pharmacology MeSH
- Pyridines pharmacology MeSH
- Pyrimidines pharmacology MeSH
- Smoothened Receptor antagonists & inhibitors MeSH
- Receptors, Transforming Growth Factor beta antagonists & inhibitors genetics MeSH
- Recombinant Proteins pharmacology MeSH
- Connective Tissue Growth Factor genetics MeSH
- Aged MeSH
- Signal Transduction drug effects MeSH
- Scleroderma, Systemic genetics metabolism MeSH
- Receptor, Transforming Growth Factor-beta Type I MeSH
- Transforming Growth Factor beta metabolism pharmacology MeSH
- Kruppel-Like Transcription Factors antagonists & inhibitors genetics 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
- Names of Substances
- Anilides MeSH
- GANT 61 MeSH Browser
- Gli2 protein, mouse MeSH Browser
- HhAntag691 MeSH Browser
- Plasminogen Activator Inhibitor 1 MeSH
- Collagen Type I MeSH
- RNA, Messenger MeSH
- Zinc Finger Protein Gli2 MeSH
- Smad3 Protein MeSH
- Protein Serine-Threonine Kinases MeSH
- Hedgehog Proteins MeSH
- Pteridines MeSH
- Pyridines MeSH
- Pyrimidines MeSH
- Smoothened Receptor MeSH
- Receptors, Transforming Growth Factor beta MeSH
- Recombinant Proteins MeSH
- Connective Tissue Growth Factor MeSH
- SD-208 MeSH Browser
- Receptor, Transforming Growth Factor-beta Type I MeSH
- Transforming Growth Factor beta MeSH
- Kruppel-Like Transcription Factors MeSH
OBJECTIVES: Hedgehog signalling plays a critical role during the pathogenesis of fibrosis in systemic sclerosis (SSc). Besides canonical hedgehog signalling with smoothened (SMO)-dependent activation of GLI transcription factors, GLI can be activated independently of classical hedgehog ligands and receptors (so-called non-canonical pathways). Here, we aimed to evaluate the role of non-canonical hedgehog signalling in SSc and to test the efficacy of direct GLI inhibitors that target simultaneously canonical and non-canonical hedgehog pathways. METHODS: The GLI inhibitor GANT-61 was used to inhibit canonical as well as non-canonical hedgehog signalling, while the SMO inhibitor vismodegib was used to selectively target canonical hedgehog signalling. Furthermore, GLI2 was selectively depleted in fibroblasts using the Cre-LoxP system. The effects of pharmacological or genetic of GLI2 on transforming growth factor-β (TGF-β) signalling were analysed in cultured fibroblasts, in bleomycin-induced pulmonary fibrosis and in mice with overexpression of a constitutively active TGF-β receptor I. RESULTS: TGF-β upregulated GLI2 in a Smad3-dependent manner and induced nuclear accumulation and DNA binding of GLI2. Fibroblast-specific knockout of GLI2 protected mice from TBRact-induced fibrosis. Combined targeting of canonical and non-canonical hedgehog signalling with direct GLI inhibitors exerted more potent antifibrotic effects than selective targeting of canonical hedgehog signalling with SMO inhibitors in experimental dermal and pulmonary fibrosis. CONCLUSIONS: Our data demonstrate that hedgehog pathways and TGF-β signalling both converge to GLI2 and that GLI2 integrates those signalling to promote tissue fibrosis. These findings may have translational implications as non-selective inhibitors of GLI2 are in clinical use and selective molecules are currently in development.
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