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The histone demethylase Jumonji domain-containing protein 3 (JMJD3) regulates fibroblast activation in systemic sclerosis
  1. Christina Bergmann1,
  2. Amelie Brandt1,
  3. Benita Merlevede1,
  4. Ludwig Hallenberger1,
  5. Clara Dees1,
  6. Thomas Wohlfahrt1,
  7. Sebastian Pötter1,
  8. Yun Zhang1,
  9. Chih-Wei Chen1,
  10. Tatiana Mallano1,
  11. Ruifang Liang1,
  12. Rosebeth Kagwiria1,
  13. Alexander Kreuter2,
  14. Ioanna Pantelaki2,
  15. Aline Bozec1,
  16. David Abraham3,
  17. Ralf Rieker4,
  18. Andreas Ramming1,
  19. Oliver Distler5,
  20. Georg Schett1,
  21. Jörg H W Distler1
  1. 1Department of Internal Medicine 3–Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Bayern, Germany
  2. 2Department of Dermatology, Venereology, and Allergology, HELIOS St Elisabeth Hospital Oberhausen, University Witten-Herdecke, Germany
  3. 3Centre for Rheumatology and Connective Tissue, University College London School of Life and Medical Sciences, London, UK
  4. 4Department of Pathology, Friedrich-Alexander Universität (FAU) Erlangen, Erlangen, Germany
  5. 5Department of Rheumaklinik, University Hospital Zurich, Zurich, Switzerland
  1. Correspondence to Christina Bergmann, Department of Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Ulmenweg 18, D-91054 Erlangen, Germany; Christina.Bergmann{at}uk-erlangen.de

Abstract

Objectives Systemic sclerosis (SSc) fibroblasts remain activated even in the absence of exogenous stimuli. Epigenetic alterations are thought to play a role for this endogenous activation. Trimethylation of histone H3 on lysine 27 (H3K27me3) is regulated by Jumonji domain-containing protein 3 (JMJD3) and ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) in a therapeutically targetable manner. The aim of this study was to explore H3K27me3 demethylases as potential targets for the treatment of fibrosis.

Methods JMJD3 was inactivated by small interfering RNA-mediated knockdown and by pharmacological inhibition with GSKJ4. The effects of targeted inactivation of JMJD3 were analysed in cultured fibroblasts and in the murine models of bleomycin-induced and topoisomerase-I (topoI)-induced fibrosis. H3K27me3 at the FRA2 promoter was analysed by ChIP.

Results The expression of JMJD3, but not of UTX, was increased in fibroblasts in SSc skin and in experimental fibrosis in a transforming growth factor beta (TGFβ)-dependent manner. Inactivation of JMJD3 reversed the activated fibroblast phenotype in SSc fibroblasts and prevented the activation of healthy dermal fibroblasts by TGFβ. Pharmacological inhibition of JMJD3 ameliorated bleomycin-induced and topoI-induced fibrosis in well-tolerated doses. JMJD3 regulated fibroblast activation in a FRA2-dependent manner: Inactivation of JMJD3 reduced the expression of FRA2 by inducing accumulation of H3K27me3 at the FRA2 promoter. Moreover, the antifibrotic effects of JMJD3 inhibition were reduced on knockdown of FRA2.

Conclusion We present first evidence for a deregulation of JMJD3 in SSc. JMJD3 modulates fibroblast activation by regulating the levels of H3K27me3 at the promoter of FRA2. Targeted inhibition of JMJD3 limits the aberrant activation of SSc fibroblasts and exerts antifibrotic effects in two murine models.

  • fibroblasts
  • systemic sclerosis
  • treatment

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Footnotes

  • Handling editor Tore K Kvien

  • Contributors CB and JHWD designed the research. CB, AB and JHWD wrote the manuscript. All authors: performed, analysed and interpreted the research.

  • Funding Grants DI 1537/5-1, DI 1537/7-1, DI 1537/8-1, DI 1537/9-1, DI 1537/11-1, DE 2414/2-1, RA 2506/3-1 and AK 144/2-1 of the German Research Foundation, CRC1181 of the German Research Foundation (project C01), grants A57, J40 and A64 of the IZKF in Erlangen, grant 2013.056.1 of the Wilhelm-Sander-Foundation, grants 2014_A47, 2014_A248 and 2014_A184 of the Else-Kröner-Fresenius-Foundation, grant 14-12-17-1-Bergmann of the ELAN-Foundation Erlangen and a Career Support Award of Medicine of the Ernst Jung Foundation, Research Award of the German Scleroderma Foundation (Deutsche Stiftung Sklerodermie).

  • Competing interests O.D. has consulted for, or has received research funding from, 4D Science, Actelion, Active Biotech, Bayer-Schering, Biogen, Biovitrium, BMS, Boehringer, EpiPharm, Ergonex, GSK, Inventiva, Medac, Novartis, Pfizer, Roche/Genentech, Sanofi/Genzyme, Serodapharm, Sinoxa and United BioSource Corporation; JHWD has consultancy relationships and/or has received research funding from Actelion, BMS, Celgene, Bayer Pharma, Boehringer Ingelheim, JB Therapeutics, Sanofi-Aventis, Novartis, UCB, GSK, Array Biopharma, Galapagos, Inventiva and Active Biotech in the area of potential treatments of SSc and is stock owner of 4D Science.

  • Ethics approval Erlangen-Nuremberg.

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

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