Composition of TWIST1 dimers regulates fibroblast activation and tissue fibrosis

Palumbo-Zerr K, Soare A, Zerr P, Liebl A, Mancuso R, Tomcik M, Sumova B, Dees C, Chen CW, Wohlfahrt T, Mallano T, Distler A, Gelse K, Mihai C, Distler O, Schett G, Distler J, Ramming A (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Annals of the Rheumatic Diseases BMJ Publishing Group

Book Volume: 76

Pages Range: 244-251

Journal Issue: 1

DOI: 10.1136/annrheumdis-2015-208470

Abstract

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).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)? receptor I.The expression of TWIST1 was increased in fibroblasts in fibrotic human and murine skin in a TGF?/SMAD3-dependent manner. TWIST1 in turn enhanced TGF?-induced fibroblast activation in a p38-dependent manner. The stimulatory effects of TWIST1 on resident fibroblasts were mediated by TWIST1 homodimers. TGF? 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.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? signalling in SSc.

Authors with CRIS profile

Pawel Zerr Department of Medicine 3 – Rheumatology and Immunology Andrea Liebl Professur für Molekulare und Experimentelle Chirurgie Clara Dees Department of Medicine 3 – Rheumatology and Immunology Tatjana Mallano Department of Medicine 3 – Rheumatology and Immunology Georg Schett Lehrstuhl für Innere Medizin III Jörg Distler Professur für Molekulare Mechanismen der Organfibrose Andreas Ramming Department of Medicine 3 – Rheumatology and Immunology

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Involved external institutions

Universitätsspital Zürich (USZ) CH Switzerland (CH) Carol Davila University of Medicine and Pharmacy / Universitatea de Medicină și Farmacie „Carol Davila” (UMF București) RO Romania (RO)

How to cite

APA:

Palumbo-Zerr, K., Soare, A., Zerr, P., Liebl, A., Mancuso, R., Tomcik, M.,... Ramming, A. (2017). Composition of TWIST1 dimers regulates fibroblast activation and tissue fibrosis. Annals of the Rheumatic Diseases, 76(1), 244-251. https://doi.org/10.1136/annrheumdis-2015-208470

MLA:

Palumbo-Zerr, Katrin, et al. "Composition of TWIST1 dimers regulates fibroblast activation and tissue fibrosis." Annals of the Rheumatic Diseases 76.1 (2017): 244-251.

BibTeX: Download