Composition of TWIST1 dimers regulates fibroblast activation and tissue fibrosis

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F17%3A10361826" target="_blank" >RIV/00216208:11110/17:10361826 - isvavai.cz</a>

Alternative codes found

RIV/00023728:_____/17:N0000027

Result on the web

<a href="http://dx.doi.org/10.1136/annrheumdis-2015-208470" target="_blank" >http://dx.doi.org/10.1136/annrheumdis-2015-208470</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1136/annrheumdis-2015-208470" target="_blank" >10.1136/annrheumdis-2015-208470</a>

Result language

angličtina

Original language name

Composition of TWIST1 dimers regulates fibroblast activation and tissue fibrosis

Original language description

Objectives TWIST1 is a member of the class B of basic helix-loop-helix transcription factors that regulates cell lineage determination and differentiation and has been implicated in epithelial-to-mesenchymal transition. Here, we aimed to investigate the role of TWIST1 for the activation of resident fibroblasts in systemic sclerosis (SSc). Methods The expression of Twist1 in fibroblasts was modulated by forced overexpression or siRNA-mediated knockdown. Interaction of Twist1, E12 and inhibitor Of differentiation (Id) was analysed by co-immunoprecipitation. The role of Twist1 in vivo was evaluated using inducible, conditional knockout mice with either ubiquitous or fibroblast-specific depletion of Twist1. Mice were either challenged with bleomycin or overexpressing a constitutively active transforming growth factor (TGF)beta receptor I. Result The expression of TWIST1 was increased in fibroblasts in fibrotic human and murine skin in a TGF beta/SMAD3-dependent manner. TWIST1 in turn enhanced TGF beta-induced fibroblast activation in a p38-dependent manner. The stimulatory effects of TWIST1 on resident fibroblasts were mediated by TWIST1 homodimers. TGF beta promotes the formation of TWIST1 homodimers by upregulation of TWIST1 and by induction of inhibitor of DNA-binding proteins, which have high affinity for E12/E47 and compete against TWIST1 for E12/E47 binding. Mice with selective depletion of Twist1 in fibroblasts are protected from experimental skin fibrosis in different murine models to a comparable degree as mice with ubiquitous depletion of Twist1. Conclusions Our data identify TWIST1 as a central pro-fibrotic factor in SSc, which facilitates fibroblast activation by amplifying TGF signalling. Targeting of TWIST1 may thus be a novel approach to normalise aberrant TGF beta signalling in SSc.

Czech name

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Czech description

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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

S - Specificky vyzkum na vysokych skolach

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

1

Country of publishing house

GB - UNITED KINGDOM

Number of pages

8

Pages from-to

244-251

UT code for WoS article

000392425200035

EID of the result in the Scopus database

2-s2.0-84965078966