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Inhibition of sumoylation prevents experimental fibrosis
  1. Aisa Khodzhigorova1,
  2. Alfiya Distler1,
  3. Veronika Lang1,
  4. Clara Dees1,
  5. Holm Schneider2,
  6. Christian Beyer1,
  7. Kolja Gelse3,
  8. Oliver Distler4,
  9. Georg Schett1,
  10. Jörg H W Distler1
  1. 1Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Department of Pediatrics, University of Erlangen-Nuremberg, Erlangen, Germany
  3. 3Department of Surgery, University of Erlangen-Nuremberg, Erlangen, Germany
  4. 4Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland
  1. Correspondence to Jörg H W Distler, Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen D-91054, Germany; joerg.distler{at}uk-erlangen.de

Abstract

Objectives Fibrosis is a predominant cause of death in systemic sclerosis (SSc). First epigenetic modifications have recently been shown to contribute to activation of SSc fibroblasts. Here, we investigated inhibition of sumoylation as a novel antifibrotic approach.

Methods Sumoylation was inhibited by siRNA-mediated knockdown of the Small Ubiquitin-like MOdifiers (SUMO) E2-conjugating enzyme Ubc9, which is essential for sumoylation. The effects of knockdown of Ubc9 were analysed in bleomycin-induced dermal fibrosis, and in the model of fibrosis induced by overexpression of a constitutively active TGF-beta receptor type I (TBR). SUMO-1 and phosphorylated Smad3 were detected by immunohistochemistry.

Results Increased staining for SUMO-1 was detected in patients with SSc and in experimental fibrosis. Inhibition of sumoylation exerted potent antifibrotic effects and prevented dermal thickening, myofibroblast differentiation and accumulation of collagen induced by bleomycin, or by overexpression of constitutively active TBR. Moreover, knockdown of Ubc9 reduced the accumulation of phosphorylated Smad3 in experimental fibrosis indicating that inhibition of sumoylation may normalise canonical TGF-β signalling in vivo.

Conclusions We demonstrate that inhibition of sumoylation reduces canonical TGF-β signalling and prevents experimental fibrosis in different preclinical models. These data provide first evidence that targeting of aberrant sumoylation may be a novel therapeutic approach for fibrotic diseases.

  • Fibroblasts
  • Systemic Sclerosis
  • Treatment

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    BMJ Publishing Group Ltd and European League Against Rheumatism