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Notch signalling regulates fibroblast activation and collagen release in systemic sclerosis
  1. Clara Dees1,
  2. Michal Tomcik1,2,
  3. Pawel Zerr1,
  4. Alfiya Akhmetshina1,
  5. Angelika Horn1,
  6. Katrin Palumbo1,
  7. Christian Beyer1,
  8. Jochen Zwerina1,
  9. Oliver Distler3,
  10. Georg Schett1,
  11. Jörg H W Distler1
  1. 1Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen–Nuremberg, Erlangen, Germany
  2. 2Institute of Rheumatology and Connective Tissue Research Laboratory, Department of Rheumatology of the First Faculty of Medicine, Charles University, Prague, Czech Republic
  3. 3Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland
  1. Correspondence to Dr Jörg H W Distler, Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen–Nuremberg, Erlangen, Germany; joerg.distler{at}


Background Dermal fibroblasts from patients with systemic sclerosis (SSc) release excessive amounts of collagen resulting in tissue fibrosis. The molecular mechanisms underlying this pathological activation are incompletely understood.

Objective To investigate whether Notch signalling contributes to the uncontrolled activation of fibroblasts in SSc.

Methods Activation of the Notch pathway was assessed by immunohistochemistry or Western blot for the Notch intracellular domain and the Notch ligand Jagged-1 (Jag-1) and real-time PCR for the target gene hes-1. Differentiation of resting dermal fibroblasts into myofibroblasts was assessed by staining for α-smooth muscle actin. The synthesis of collagen was quantified by real-time PCR and Sircol assays.

Results Notch signalling was activated in lesional skin of patients with SSc. The activation persisted in cultured dermal SSc fibroblasts. Stimulation of healthy dermal fibroblasts with recombinant human Jag-1-Fc chimera resulted in an SSc-like phenotype with increased release of collagen and differentiation of resting fibroblasts into myofibroblasts. Consistent with the selective activation of the Notch pathway in dermal SSc fibroblasts, DAPT or siRNA against Notch strongly reduced the basal collagen expression in SSc fibroblasts, but not in fibroblasts from healthy volunteers.

Conclusion It was shown that Notch signalling is activated in SSc and plays an important role in fibroblast activation and collagen release. Inhibition of Notch signalling might be an effective strategy to selectively prevent the aberrant activation of SSc fibroblasts.

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  • Funding The study was supported by the Deutsche Forschungsgesellschaft (DI 1537/2-1), grants A20 and A40 of the Interdisciplinary Center of Clinical Research (IZKF) in Erlangen, by the Career Support Award of Medicine of the Ernst Jung Foundation and by support of CMH Research Projects No 00000023728.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the ethics committee of the University of Erlangen.

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