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Vitamin D receptor regulates TGF-β signalling in systemic sclerosis
  1. Pawel Zerr1,
  2. Stefan Vollath1,
  3. Katrin Palumbo-Zerr1,
  4. Michal Tomcik1,2,
  5. Jingang Huang1,
  6. Alfiya Distler1,
  7. Christian Beyer1,
  8. Clara Dees1,
  9. Kolja Gela3,
  10. Oliver Distler4,
  11. Georg Schett1,
  12. Jörg H W Distler1
  1. 1Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Department of Rheumatology of the First Faculty of Medicine, Institute of Rheumatology, Charles University, Prague, Czech Republic
  3. 3Department of Orthopedic Trauma 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 Dr Jörg Distler, Department of Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Ulmenweg 18, Erlangen D-91054, Germany; Joerg.distler{at}uk-erlangen.de

Abstract

Background Vitamin D receptor (VDR) is a member of the nuclear receptor superfamily. Its ligand, 1,25-(OH)2D, is a metabolically active hormone derived from vitamin D3. The levels of vitamin D3 are decreased in patients with systemic sclerosis (SSc). Here, we aimed to analyse the role of VDR signalling in fibrosis.

Methods VDR expression was analysed in SSc skin, experimental fibrosis and human fibroblasts. VDR signalling was modulated by siRNA and with the selective agonist paricalcitol. The effects of VDR on Smad signalling were analysed by reporter assays, target gene analyses and coimmunoprecipitation. The effects of paricalcitol were evaluated in the models of bleomycin-induced fibrosis and fibrosis induced by overexpression of a constitutively active transforming growth factor-β (TGF-β) receptor I (TBRICA).

Results VDR expression was decreased in fibroblasts of SSc patients and murine models of SSc in a TGF-β-dependent manner. Knockdown of VDR enhanced the sensitivity of fibroblasts towards TGF-β. In contrast, activation of VDR by paricalcitol reduced the stimulatory effects of TGF-β on fibroblasts and inhibited collagen release and myofibroblast differentiation. Paricalcitol stimulated the formation of complexes between VDR and phosphorylated Smad3 in fibroblasts to inhibit Smad-dependent transcription. Preventive and therapeutic treatment with paricalcitol exerted potent antifibrotic effects and ameliorated bleomycin- as well as TBRICA-induced fibrosis.

Conclusions We characterise VDR as a negative regulator of TGF-β/Smad signalling. Impaired VDR signalling with reduced expression of VDR and decreased levels of its ligand may thus contribute to hyperactive TGF-β signalling and aberrant fibroblast activation in SSc.

  • Fibroblasts
  • Systemic Sclerosis
  • Treatment

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