title: Estradiol promotes the development of a fibrotic phenotype and is increased in the serum of patients with systemic sclerosis.
abstract: BACKGROUND
  Systemic sclerosis (SSc) is more prevalent in women. Our goal is to determine the effects of 17β-estradiol (E2) on the development of fibrosis and to compare circulating levels of estrogens in SSc patients and healthy controls.
  
  
  METHODS
  Using primary human dermal fibroblasts, we evaluated the effect of E2 on fibronectin (FN) expression with and without the estrogen receptor (ER) antagonist ICI 182,780, inhibitors of signaling, propyl-pyrazole-triol, an ERα specific ligand, and genistein, an ERβ selective ligand, to identify the signaling pathways mediating E2's effect. We confirmed the fibrotic effect of E2 in human skin using an ex vivo organ culture model. Lastly, we measured levels of E2 and estrone in serum samples from SSc patients with diffuse cutaneous involvement and healthy controls using mass spectrometry.
  
  
  RESULTS
  E2 increased expression of FN in dermal fibroblasts. ICI 182,780, inositol-1,4,5-triphosphate inhibitor, and p38 mitogen-activated protein kinase inhibitor blocked the effects of E2 on FN. Propyl-pyrazole-triol, but not genistein, significantly increased FN expression. Ex vivo, E2 induced fibrosis of human skin. The effects of E2 were abrogated by ICI 182,780. Circulating levels of E2 and estrone were significantly increased in sera of patients with diffuse cutaneous SSc.
  
  
  CONCLUSIONS
  Our findings implicate estrogens in the fibrotic process and may explain the preponderance of SSc in women. ICI 182,780 or other ER signaling antagonists may be effective agents for the treatment of fibrosis.
authors.forename: Keiko
authors.initials: K
authors.lastname: Aida-Yasuoka
authors.forename: Christine
authors.initials: C
authors.lastname: Peoples
authors.forename: Hidekata
authors.initials: H
authors.lastname: Yasuoka
authors.forename: Pamela
authors.initials: P
authors.lastname: Hershberger
authors.forename: Katelynn
authors.initials: K
authors.lastname: Thiel
authors.forename: Jane A
authors.initials: JA
authors.lastname: Cauley
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Medsger
authors.forename: Carol A
authors.initials: CA
authors.lastname: Feghali-Bostwick
mesh_terms: D000368:Aged; D015153:Blotting, Western; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D004958:Estradiol / Q000097:blood*; D065171:Estrogen Receptor Antagonists / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005353:Fibronectins / Q000096:biosynthesis / Q000187:drug effects; D005355:Fibrosis / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012595:Scleroderma, Systemic / Q000097:blood* / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D053719:Tandem Mass Spectrometry
chemical_list: D065171:Estrogen Receptor Antagonists; D005353:Fibronectins; D004958:Estradiol