title: Notch signalling regulates fibroblast activation and collagen release in systemic sclerosis.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen–Nuremberg, Germany.
authors: Clara
authors: C
authors: Dees
authors: Michal
authors: M
authors: Tomcik
authors: Pawel
authors: P
authors: Zerr
authors: Alfiya
authors: A
authors: Akhmetshina
authors: Angelika
authors: A
authors: Horn
authors: Katrin
authors: K
authors: Palumbo
authors: Christian
authors: C
authors: Beyer
authors: Jochen
authors: J
authors: Zwerina
authors: Oliver
authors: O
authors: Distler
authors: Georg
authors: G
authors: Schett
authors: Jörg H W
authors: JH
authors: Distler
mesh_terms: D000328:Adult; D000368:Aged; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D004151:Dipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008875:Middle Aged; D058628:Myofibroblasts / Q000473:pathology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012595:Scleroderma, Systemic / Q000378:metabolism / Q000473:pathology*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D002135:Calcium-Binding Proteins; D004151:Dipeptides; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D051880:Receptors, Notch; D011994:Recombinant Proteins; D000072099:Serrate-Jagged Proteins; D003094:Collagen; D053829:Amyloid Precursor Protein Secretases