ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 753

The Histone Demethylase Jumonji Domain-Containing Protein 3 (JMJD3) As Central Mediator of Fibroblast Activation

Christina Bergmann1, Amelie Brandt1, Clara Dees2, Yun Zhang3, Chih-Wei Chen4, Tatjana Mallano5, Thomas Wohlfahrt6, Ruifang Liang7, Rosebeth Kagwiria1, Aline Bozec8, Ralf Rieker9, David Abraham10, Andreas Ramming11, Oliver Distler12, Georg Schett13 and Jörg Distler14, 1Department of Internal Medicine 3 and Institute for Clinical Immunology, Friedrich-Alexander-University of Erlangen-Nuremberg and University Hospital Erlangen, Erlangen, Germany, 2Department of Internal Medicine 3 and Institute for Clinical Immunology,, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany, 3Department of Internal Medicine 3 and Institute for Clinical Immunology, Department of Internal Medicine 3 and Institute for Clinical Immunology, Friedrich-Alexander-University of Erlangen-Nuremberg and University Hospital Erlangen, Erlangen, Germany, 4Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany, Erlangen, Germany, 5Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany, 6Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany, 7Department of Internal Medicine 3 – Rheumatology and Immunology, Universitätsklinikum Erlangen, Department of Internal Medicine 3 and Institute for Clinical Immunology, Friedrich-Alexander-University of Erlangen-Nuremberg and University Hospital Erlangen, Erlangen, Germany, 8Department Clinic of Medicine 3 - Immunology und Rheumatology, University of Erlangen-Nürnberg, Department Clinic of Medicine 3 - Immunology and Rheumatology, Erlangen, Germany, Erlangen, Germany, 9Department of Pathology, University Clinic Erlangen, Erlangen, Germany, 10Centre for Rheumatology and Connective Tissue, UCL School of Life and Medical Sciences, London, London, United Kingdom, 11Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany, 12Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland, 13Department of Internal Medicine 3 – Rheumatology and Immunology, Department of Internal Medicine 3 and Institute for Clinical Immunology, Friedrich-Alexander-University of Erlangen-Nuremberg and University Hospital Erlangen, Erlangen, Germany, 14Department of Internal Medicine 3 – Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: ,

Session Information

Date: Sunday, November 5, 2017

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's – Pathogenesis, Animal Models and Genetics Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose:

Epigenetic modifications are key drivers of chronic fibroblast activation. Trimethylation of histone 3 at lysine residue K27 (H3K27me3) is a repressive modification, that is implicated in fibroblasts activation. Inhibition of H3K27 trimethylation promotes fibroblast activation. However, the role of H3K27me3 demethylases in fibrosing disorders has not been characterized. The aim of this study is to characterize the role of JMJD3 in as potential drug target in fibrotic disease.

Methods:

siRNA mediated knockdown and GSKJ4 were used to target JMJD3 in vitro and in vivo. Fibroblast activation was analyzed by quantifying collagen synthesis and release, stress fiber formation and by scratch assays. The effects of GSKJ4 on experimental fibrosis were assessed in the Topoisomerase I-mouse model of skin and lung fibrosis and in Bleomycin-induced skin fibrosis. Inflammatory infiltrates in the skin were assessed by immunofluorescence staining. H3K27me3 of target genes was analyzed by ChIP.

Results: We demonstrated increased expression of JMJD3 in fibrotic diseases with increased expression of JMJD3 in the skin of SSc patients and in tissue from patients with liver fibrosis and idiopathic pulmonary fibrosis compared to healthy controls. The overexpression was particularly pronounced in fibroblasts. JMJD3 was also overexpressed in dermal and pulmonary fibrosis in TopoI-induced fibrosis and in bleomycin-induced skin fibrosis. Targeting JMJD3 in vitro ameliorated the activated fibroblast phenotype with decreased collagen release and reduced expression of myofibroblast markers. By screening for several profibrotic pathways, we identified FRA2 as central downstream mediator of JMJD3 mediated fibroblast activation. H3K27me3 at the FRA2 promoter was reduced by TGFβ stimulation, which resulted in increased expression of FRA2. Treatment with GSKJ4 prevented the TGFβ-induced downregulation of H3K27me3 at the FRA2 promoter. The functional importance of FRA2 for JMJD3 regulated fibroblast activation was further highlighted by knockdown studies: Upon knockdown of FRA2, GSKJ4 loses its inhibitory function on collagen secretion. In vivo, we observed potent antifibrotic effects of JMJD3 inhibition on dermal and pulmonary fibrosis with reduced fibrotic tissue remodeling, decreased collagen content and impaired differentiation of resting fibroblasts into myofibroblasts. As GSKJ4 treatment had no effect on B- cell counts in experimental fibrosis. However, GSKJ4 treatment resulted in a slight reduction of T-cell counts.

Conclusion:

We present first evidence for a dysregulation of JMJD3 in SSc. JMJD3 regulates fibroblast activation by modulating the levels of H3K27me3 at the FRA2 promoter. Targeted inhibition of JMJD3 reduces the aberrant activation of SSc fibroblasts and has strong antifibrotic effects in murine models of SSc.

Disclosure: C. Bergmann, None; A. Brandt, None; C. Dees, None; Y. Zhang, None; C. W. Chen, None; T. Mallano, None; T. Wohlfahrt, None; R. Liang, None; R. Kagwiria, None; A. Bozec, None; R. Rieker, None; D. Abraham, None; A. Ramming, None; O. Distler, 4 D Science, Actelion, Active Biotec, Bayer, Biogen Idec, Boehringer Ingelheim Pharma, BMS, ChemomAb, EpiPharm, Ergonex, espeRare foundation, GSK,Roche-Genentech, Inventiva, Lilly, medac, MedImmune, Mitsubishi Tanabe, Pharmacyclics, Pfizer, Sanofi, Seroda, 2; G. Schett, None; J. Distler, 4D Science, 1,Anamar Medical, Active Biotech, Array Biopma, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, GSK, Novartis, Sanofi-Aventis, UCB, 2,Actelion Pharmaceuticals US, Active Biotech, Anamar, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi, UCB, 5.

To cite this abstract in AMA style:

Bergmann C, Brandt A, Dees C, Zhang Y, Chen CW, Mallano T, Wohlfahrt T, Liang R, Kagwiria R, Bozec A, Rieker R, Abraham D, Ramming A, Distler O, Schett G, Distler J. The Histone Demethylase Jumonji Domain-Containing Protein 3 (JMJD3) As Central Mediator of Fibroblast Activation [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/the-histone-demethylase-jumonji-domain-containing-protein-3-jmjd3-as-central-mediator-of-fibroblast-activation/. Accessed .

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