The transcription factor GLI2 as a downstream mediator of transforming growth factor-?-induced fibroblast activation in SSc

Liang R, Sumova B, Cordazzo C, Mallano T, Zhang Y, Wohlfahrt T, Dees C, Krasowska D, Michalska-Jakubus M, Distler O, Schett G, Senolt L, Distler J, Ramming A (2016)


Publication Type: Journal article

Publication year: 2016

Journal

DOI: 10.1136/annrheumdis-2016-209698

Abstract

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.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-? (TGF-?) signalling were analysed in cultured fibroblasts, in bleomycin-induced pulmonary fibrosis and in mice with overexpression of a constitutively active TGF-? receptor I.TGF-? upregulated GLI2 in a Smad3-dependent manner and induced nuclear accumulation and DNA binding of GLI2. Fibroblast-specific knockout of GLI2 protected mice from TBR(act)-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.Our data demonstrate that hedgehog pathways and TGF-? 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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APA:

Liang, R., Sumova, B., Cordazzo, C., Mallano, T., Zhang, Y., Wohlfahrt, T.,... Ramming, A. (2016). The transcription factor GLI2 as a downstream mediator of transforming growth factor-?-induced fibroblast activation in SSc. Annals of the Rheumatic Diseases. https://dx.doi.org/10.1136/annrheumdis-2016-209698

MLA:

Liang, Ruifang, et al. "The transcription factor GLI2 as a downstream mediator of transforming growth factor-?-induced fibroblast activation in SSc." Annals of the Rheumatic Diseases (2016).

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