title: Hedgehog signaling controls fibroblast activation and tissue fibrosis in systemic sclerosis.
abstract: OBJECTIVE
  Hedgehog signaling not only plays crucial roles during human development but also has been implicated in the pathogenesis of several diseases in adults. The aim of the present study was to investigate the role of the hedgehog pathway in fibroblast activation in systemic sclerosis (SSc).
  
  
  METHODS
  Activation of the hedgehog pathway was analyzed by immunohistochemistry and real-time polymerase chain reaction (PCR). The effects of sonic hedgehog (SHH) on collagen synthesis were analyzed by reporter assays, real-time PCR, and Sircol assays. Myofibroblast differentiation was assessed by quantification of α-smooth muscle actin and stress fiber staining. The role of hedgehog signaling in vivo was analyzed by adenoviral overexpression of SHH and using mice lacking 1 allele of the gene for inhibitory receptor Patched homolog 1 (Ptch(+/-) mice).
  
  
  RESULTS
  SHH was overexpressed and resulted in activation of hedgehog signaling in patients with SSc, with accumulation of the transcription factors Gli-1 and Gli-2 and increased transcription of hedgehog target genes. Activation of hedgehog signaling induced an activated phenotype in cultured fibroblasts, with differentiation of resting fibroblasts into myofibroblasts and increased release of collagen. Adenoviral overexpression of SHH in the skin of mice was sufficient to induce skin fibrosis. Moreover, Ptch(+/-) mice with increased hedgehog signaling were more sensitive to bleomycin-induced dermal fibrosis.
  
  
  CONCLUSIONS
  We demonstrated that the hedgehog pathway is activated in patients with SSc. Hedgehog signaling potently stimulates the release of collagen and myofibroblast differentiation in vitro and is sufficient to induce fibrosis in vivo. These findings identify the hedgehog cascade as a profibrotic pathway in SSc.
authors.affiliation: University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Horn
authors.forename: Katrin
authors.initials: K
authors.lastname: Palumbo
authors.forename: Cinzia
authors.initials: C
authors.lastname: Cordazzo
authors.forename: Clara
authors.initials: C
authors.lastname: Dees
authors.forename: Alfiya
authors.initials: A
authors.lastname: Akhmetshina
authors.forename: Michal
authors.initials: M
authors.lastname: Tomcik
authors.forename: Pawel
authors.initials: P
authors.lastname: Zerr
authors.forename: Jerome
authors.initials: J
authors.lastname: Avouac
authors.forename: Johannes
authors.initials: J
authors.lastname: Gusinde
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
authors.forename: Hermine
authors.initials: H
authors.lastname: Roudaut
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Traiffort
authors.forename: Martial
authors.initials: M
authors.lastname: Ruat
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; D000368:Aged; D000818:Animals; D001761:Bleomycin / Q000009:adverse effects; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis / Q000139:chemically induced; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008875:Middle Aged; D023421:Models, Animal; D015513:Oncogene Proteins / Q000378:metabolism; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D015534:Trans-Activators / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology; D000071676:Zinc Finger Protein GLI1
chemical_list: D053823:Hedgehog Proteins; D015513:Oncogene Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C509239:SHH protein, human; C465570:Shh protein, mouse; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1; D001761:Bleomycin; D003094:Collagen