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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F17%3A10362074" target="_blank" >RIV/00216208:11110/17:10362074 - isvavai.cz</a>

Alternative codes found

RIV/00023728:_____/17:N0000098

Result on the web

<a href="http://dx.doi.org/10.1136/annrheumdis-2016-209698" target="_blank" >http://dx.doi.org/10.1136/annrheumdis-2016-209698</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1136/annrheumdis-2016-209698" target="_blank" >10.1136/annrheumdis-2016-209698</a>

Result language

angličtina

Original language name

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

Original language description

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-beta (TGF-beta) signalling were analysed in cultured fibroblasts, in bleomycin-induced pulmonary fibrosis and in mice with overexpression of a constitutively active TGF-beta receptor I. Results TGF-beta 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-beta 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.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30226 - Rheumatology

Project

—

Continuities

V - Vyzkumna aktivita podporovana z jinych verejnych zdroju

Publication year

2017

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Annals of the Rheumatic Diseases

ISSN

0003-4967

e-ISSN

—

Volume of the periodical

76

Issue of the periodical within the volume

4

Country of publishing house

GB - UNITED KINGDOM

Number of pages

9

Pages from-to

756-764

UT code for WoS article

000396856100022

EID of the result in the Scopus database

2-s2.0-84994805525