title: Inhibition of Notch signaling prevents experimental fibrosis and induces regression of established fibrosis.
abstract: OBJECTIVE
  Tissue fibrosis caused by pathologic activation of fibroblasts with increased synthesis of extracellular matrix components is a major hallmark of systemic sclerosis (SSc). Notch signaling regulates tissue differentiation, and abnormal activation of Notch signaling has been implicated in the pathogenesis of various malignancies. The present study was undertaken to investigate the role of Notch signaling in SSc and to evaluate the therapeutic potential of Notch inhibition for the treatment of fibrosis.
  
  
  METHODS
  Activation of the Notch pathways was analyzed by staining for the Notch intracellular domain (NICD) and quantification of levels of HES-1 messenger RNA. In the mouse model of bleomycin-induced dermal fibrosis and in tight skin 1 mice, Notch signaling was inhibited by the γ-secretase inhibitor DAPT and by overexpression of a Notch-1 antisense construct.
  
  
  RESULTS
  Notch signaling was activated in SSc in vivo, with accumulation of the NICD and increased transcription of the target gene HES-1. Overexpression of a Notch antisense construct prevented bleomycin-induced fibrosis and hypodermal thickening in tight skin 1 mice. Potent antifibrotic effects were also obtained with DAPT treatment. In addition to prevention of fibrosis, targeting of Notch signaling resulted in almost complete regression of established experimental fibrosis.
  
  
  CONCLUSIONS
  The present results demonstrate that pharmacologic as well as genetic inhibition of Notch signaling exerts potent antifibrotic effects in different murine models of SSc. These findings might have direct translational implications because different inhibitors of the γ-secretase complex are available and have yielded promising results in cancer trials.
authors.affiliation: University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Clara
authors.initials: C
authors.lastname: Dees
authors.forename: Pawel
authors.initials: P
authors.lastname: Zerr
authors.forename: Michal
authors.initials: M
authors.lastname: Tomcik
authors.forename: Christian
authors.initials: C
authors.lastname: Beyer
authors.forename: Angelika
authors.initials: A
authors.lastname: Horn
authors.forename: Alfiya
authors.initials: A
authors.lastname: Akhmetshina
authors.forename: Katrin
authors.initials: K
authors.lastname: Palumbo
authors.forename: Nicole
authors.initials: N
authors.lastname: Reich
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
authors.forename: Michael
authors.initials: M
authors.lastname: Sticherling
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
mesh_terms: D000328:Adult; D000818:Animals; D001761:Bleomycin; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D051880:Receptors, Notch / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000502:physiology*; D018709:Statistics, Nonparametric
chemical_list: D051880:Receptors, Notch; D001761:Bleomycin