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

Beitrag in einer Fachzeitschrift


Details zur Publikation

Autor(en): Zhang Y, Pötter S, Chen CW, Liang Rf, Gelse K, Ludolph I, Horch RE, Distler O, Schett G, Distler J, Dees C
Zeitschrift: Annals of the Rheumatic Diseases
Jahr der Veröffentlichung: 2018
Band: 77
Heftnummer: 5
Seitenbereich: 744-751
ISSN: 0003-4967


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.


FAU-Autoren / FAU-Herausgeber

Dees, Clara Dr. rer. nat.
Medizinische Klinik 3 - Rheumatologie und Immunologie
Distler, Jörg PD Dr.
Heisenberg-Professur für Molekulare Mechanismen der Organfibrose
Horch, Raymund E. Prof. Dr.
Professur für Plastische Chirurgie und Handchirurgie
Liang, Rui fang
Professur für Molekulare und Experimentelle Chirurgie
Pötter, Sebastian
Medizinische Klinik 3 - Rheumatologie und Immunologie
Schett, Georg Prof. Dr. med.
Lehrstuhl für Innere Medizin III
Zhang, Yun Dr. rer. nat.
Medizinische Klinik 3 - Rheumatologie und Immunologie


Autor(en) der externen Einrichtung(en)
Universitätsspital Zürich (USZ)


Zitierweisen

APA:
Zhang, Y., Pötter, S., Chen, C.-W., Liang, R.f., 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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Zuletzt aktualisiert 2018-20-11 um 11:38