You are here

Article Text

Article menu
Download PDFPDF
Basic and translational research
Extended report
Poly(ADP-ribose) polymerase-1 regulates fibroblast activation in systemic sclerosis
  1. Yun Zhang1,
  2. Sebastian Pötter1,
  3. Chih-Wei Chen1,
  4. Ruifang Liang1,
  5. Kolja Gelse2,
  6. Ingo Ludolph3,
  7. Raymund E Horch3,
  8. Oliver Distler4,
  9. Georg Schett1,
  10. Jörg H W Distler1,
  11. Clara Dees1
  1. 1 Department of Internal Medicine 3 for Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital of Erlangen, Erlangen, Germany
  2. 2 Department of Trauma Surgery, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital of Erlangen, Erlangen, Germany
  3. 3 Department of Plastic and Hand Surgery, Laboratory for Tissue Engineering and Regenerative Medicine, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), University Hospital of Erlangen, Erlangen, Germany
  4. 4 Research of Systemic Autoimmune Diseases, University Hospital Zurich, Zurich, Switzerland
  1. Correspondence to Clara Dees, Department of Internal Medicine 3 for Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital of Erlangen, Erlangen 91054, Germany; clara.dees{at}uk-erlangen.de

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.

  • fibroblasts
  • systemic sclerosis
  • cytokines

https://doi.org/10.1136/annrheumdis-2017-212265

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    View Full Text

    Footnotes

    • JHWD and CD contributed equally.

    • Handling editor Tore K Kvien

    • Contributors YZ, JHWD and CD designed the study. YZ, SP, C-WC, RL and CD were involved in acquisition of data. YZ, SP, C-WC, RL, OD, GS, JHWD and CD were involved in interpretation of data. YZ, SP, JHWD and CD prepared the manuscript. KG, IL and REH provided essential material.

    • Funding DE 2414/2-1, DI 1537/5-1, DI 1537/7-1, DI 1537/8-1, DI 1537/9-1 and AK 144/1-1 of the Deutsche Forschungsgemeinschaft, grants J39 and A57 of the IZKF in Erlangen, the ELAN-Program of the University of Erlangen-Nuremberg and the Career Support Award of Medicine of the Ernst Jung Foundation.

    • Competing interests OD has consultancy relationships and/or has received research funding from Actelion, Pfizer, Ergonex, BMS, Sanofi-Aventis, United BioSource Corporation, medac, Biovitrium, Boehringer Ingelheim, Novartis, 4D Science and Active Biotech in the area of potential treatments of SSc; JHWD has consultancy relationships and/or has received research funding from Actelion, Pfizer, Ergonex, BMS, Celgene, Bayer Pharma, Boehringer Ingelheim, JB Therapeutics, Sanofi-Aventis, Novartis, UCB, GSK, Array Biopharma and Active Biotech in the area of potential treatments of SSc and is stock owner of 4D Science GmbH.

    • Ethics approval Local ethical review board.

    • Provenance and peer review Not commissioned; externally peer reviewed.