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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

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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.

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