Poly(ADP-ribose) polymerase-1 regulates fibroblast activation in systemic sclerosis

Zhang Y, Pötter S, Chen CW, Liang R, Gelse K, Ludolph I, Horch RE, Distler O, Schett G, Distler J, Dees C (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Annals of the Rheumatic Diseases BMJ Publishing Group

Book Volume: 77

Pages Range: 744-751

Journal Issue: 5

DOI: 10.1136/annrheumdis-2017-212265

Abstract

OBJECTIVES: The enzyme poly(ADP-ribose) polymerase-1 (PARP-1) transfers negatively charged ADP-ribose units to target proteins. This modification can have pronounced regulatory effects on target proteins. Recent studies showed that PARP-1 can poly(ADP-ribosyl)ate (PARylate) Smad proteins. However, the role of PARP-1 in the pathogenesis of systemic sclerosis (SSc) has not been investigated. METHODS: The expression of PARP-1 was determined by quantitative PCR and immunohistochemistry. DNA methylation was analysed by methylated DNA immunoprecipitation assays. Transforming growth factor-β (TGFβ) signalling was assessed using reporter assays, chromatin immunoprecipitation assays and target gene analysis. The effect of PARP-1 inactivation was investigated in bleomycin-induced and topoisomerase-induced fibrosis as well as in tight-skin-1 (Tsk-1) mice. RESULTS: The expression of PARP-1 was decreased in patients with SSc, particularly in fibroblasts. The promoter of PARP-1 was hypermethylated in SSc fibroblasts and in TGFβ-stimulated normal fibroblasts. Inhibition of DNA methyltransferases (DNMTs) reduced the promoter methylation and reactivated the expression of PARP-1. Inactivation of PARP-1 promoted accumulation of phosphorylated Smad3, enhanced Smad-dependent transcription and upregulated the expression of TGFβ/Smad target genes. Inhibition of PARP-1 enhanced the effect of TGFβ on collagen release and myofibroblast differentiation in vitro and exacerbated experimental fibrosis in vivo. PARP-1 deficiency induced a more severe fibrotic response to bleomycin with increased dermal thickening, hydroxyproline content and myofibroblast counts. Inhibition of PARylation also exacerbated fibrosis in Tsk-1 mice and in mice with topoisomerase-induced fibrosis. CONCLUSION: PARP-1 negatively regulates canonical TGFβ signalling in experimental skin fibrosis. The downregulation of PARP-1 in SSc fibroblasts may thus directly contribute to hyperactive TGFβ signalling and to persistent fibroblast activation in SSc.

Authors with CRIS profile

Yun Zhang Department of Medicine 3 – Rheumatology and Immunology Sebastian Pötter Department of Medicine 3 – Rheumatology and Immunology Ruifang Liang Professur für Molekulare und Experimentelle Chirurgie Ingo Ludolph Department of Plastic and Hand Surgery Raymund Horch Professur für Plastische Chirurgie und Handchirurgie Georg Schett Lehrstuhl für Innere Medizin III Jörg Distler Professur für Molekulare Mechanismen der Organfibrose Clara Dees Department of Medicine 3 – Rheumatology and Immunology

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Involved external institutions

Universitätsspital Zürich (USZ) CH Switzerland (CH)

How to cite

APA:

Zhang, Y., Pötter, S., Chen, C.-W., Liang, R., Gelse, K., Ludolph, I.,... Dees, C. (2018). Poly(ADP-ribose) polymerase-1 regulates fibroblast activation in systemic sclerosis. Annals of the Rheumatic Diseases, 77(5), 744-751. https://dx.doi.org/10.1136/annrheumdis-2017-212265

MLA:

Zhang, Yun, et al. "Poly(ADP-ribose) polymerase-1 regulates fibroblast activation in systemic sclerosis." Annals of the Rheumatic Diseases 77.5 (2018): 744-751.

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