title: Differential Expression of Hedgehog and Snail in Cutaneous Fibrosing Disorders: Implications for Targeted Inhibition.
abstract: OBJECTIVE
  To examine Hedgehog signaling in cutaneous fibrosing disorders for which effective approved therapies are lacking, expand our knowledge of pathophysiology, and explore the rationale for targeted inhibition.
  
  
  METHODS
  Stain intensity and percentage of cells staining for Sonic hedgehog (Shh), Indian hedgehog (Ihh), Patched (Ptch), glycogen synthase kinase 3 β (GSK3-β), β-catenin, and Snail were evaluated in human skin biopsy specimens of keloid, hypertrophic scar (Hscar), scleroderma, nephrogenic systemic fibrosis (NSF), scar, and normal skin using a tissue microarray.
  
  
  RESULTS
  Ihh, but not Shh, was detected in a significantly larger proportion of cells for all case types. Ptch, GSK3-β, and β-catenin showed a gradient of expression: highest in NSF and keloid; moderate in normal skin, scar, and Hscar; and lowest in scleroderma. Snail expression was binary: low in normal skin but high in all fibrosing conditions studied.
  
  
  CONCLUSIONS
  Differential overexpression of Hedgehog and Snail in cutaneous fibrosing disorders demonstrates a role for targeted inhibition. Ptch, GSK3-β, and β-catenin can help differentiate scleroderma from NSF in histologically subtle cases. Differences in expression between keloid and hypertrophic scar support the concept that they are pathophysiologically distinct disorders. Our findings implicate Snail as a target for the prevention of fibrogenesis or fibrosis progression and may offer a means to assess response to therapy.
authors.affiliation: From the Dermatopathology Unit, Pathology Service, Massachusetts General Hospital and Harvard Medical School, Boston.
authors.forename: Amrita
authors.initials: A
authors.lastname: Goyal
authors.affiliation: From the Dermatopathology Unit, Pathology Service, Massachusetts General Hospital and Harvard Medical School, Boston.
authors.forename: Katy R
authors.initials: KR
authors.lastname: Linskey
authors.affiliation: Division of Rheumatology, Department of Medicine, UMass Memorial Medical Center and University of Massachusetts Medical School, Worcester.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kay
authors.affiliation: From the Dermatopathology Unit, Pathology Service, Massachusetts General Hospital and Harvard Medical School, Boston.
authors.forename: Lyn M
authors.initials: LM
authors.lastname: Duncan
authors.affiliation: From the Dermatopathology Unit, Pathology Service, Massachusetts General Hospital and Harvard Medical School, Boston rmnazarian@partners.org.
authors.forename: Rosalynn M
authors.initials: RM
authors.lastname: Nazarian
mesh_terms: D002921:Cicatrix / Q000378:metabolism / Q000473:pathology; D017439:Cicatrix, Hypertrophic / Q000378:metabolism / Q000473:pathology; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D007627:Keloid / Q000378:metabolism / Q000473:pathology; D054989:Nephrogenic Fibrosing Dermopathy / Q000378:metabolism / Q000473:pathology; D000072079:Patched Receptors / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000378:metabolism / Q000473:pathology; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D012871:Skin Diseases / Q000378:metabolism* / Q000473:pathology; D000071250:Snail Family Transcription Factors / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D053823:Hedgehog Proteins; D000072079:Patched Receptors; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta
keywords: Dermatopathology; Fibrosis; Hedgehog; Scleroderma; Snail