title: Inhibition of hedgehog signalling prevents experimental fibrosis and induces regression of established fibrosis.
abstract: OBJECTIVE
  Tissue fibrosis is a leading cause of death in patients with systemic sclerosis (SSc). Effective antifibrotic treatments are not available. Here, the authors investigated inhibition of hedgehog signalling by targeting Smoothened (Smo) as a novel antifibrotic approach.
  
  
  METHODS
  The activation status of the hedgehog pathway was assessed by immunohistochemistry for Gli transcription factors and by quantification of hedgehog target genes. Hedgehog signalling was inhibited by the selective inhibitor LDE223 and by small interfering RNA against Smo in the models of bleomycin-induced dermal fibrosis and in tight-skin-1 mice.
  
  
  RESULTS
  Hedgehog signalling is activated in SSc and in murine models of SSc. Inhibition of Smo either by LDE223 or by small interfering RNA prevented dermal thickening, myofibroblast differentiation and accumulation of collagen upon challenge with bleomycin. Targeting Smo also exerted potent antifibrotic effects in tight-skin-1 mice and did prevent progression of fibrosis and induced regression of pre-established fibrosis.
  
  
  CONCLUSIONS
  Inhibition of hedgehog signalling exerted potent antifibrotic effects in preclinical models of SSc in both preventive and therapeutic settings. These findings might have direct translational implications because inhibitors of Smo are already available and yielded promising results in initial clinical trials.
authors.affiliation: Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Horn
authors.forename: Trayana
authors.initials: T
authors.lastname: Kireva
authors.forename: Katrin
authors.initials: K
authors.lastname: Palumbo-Zerr
authors.forename: Clara
authors.initials: C
authors.lastname: Dees
authors.forename: Michal
authors.initials: M
authors.lastname: Tomcik
authors.forename: Cinzia
authors.initials: C
authors.lastname: Cordazzo
authors.forename: Pawel
authors.initials: P
authors.lastname: Zerr
authors.forename: Alfiya
authors.initials: A
authors.lastname: Akhmetshina
authors.forename: Martial
authors.initials: M
authors.lastname: Ruat
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
authors.forename: Christian
authors.initials: C
authors.lastname: Beyer
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D001761:Bleomycin / Q000633:toxicity; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D012595:Scleroderma, Systemic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D012871:Skin Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000072086:Smoothened Receptor
chemical_list: D001713:Biphenyl Compounds; C571088:LDE223; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D001761:Bleomycin