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Estradiol promotes the development of a fibrotic phenotype and is increased in the serum of patients with systemic sclerosis

Aida-Yasuoka, K and Peoples, C and Yasuoka, H and Hershberger, P and Thiel, K and Cauley, JA and Medsger, TA and Feghali-Bostwick, CA (2013) Estradiol promotes the development of a fibrotic phenotype and is increased in the serum of patients with systemic sclerosis. Arthritis Research and Therapy, 15 (1). ISSN 1478-6354

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Abstract

Introduction: 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.Conclusion: 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. © 2013 Aida-Yasuoka et al.; licensee BioMed Central Ltd.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Aida-Yasuoka, K
Peoples, C
Yasuoka, H
Hershberger, P
Thiel, K
Cauley, JAJCauley@edc.pitt.eduJCAULEY
Medsger, TAtam8@pitt.eduTAM8
Feghali-Bostwick, CA
Date: 10 January 2013
Date Type: Publication
Journal or Publication Title: Arthritis Research and Therapy
Volume: 15
Number: 1
DOI or Unique Handle: 10.1186/ar4140
Schools and Programs: Graduate School of Public Health > Epidemiology
School of Medicine > Critical Care Medicine
School of Medicine > Immunology
School of Medicine > Medicine
Refereed: Yes
ISSN: 1478-6354
Date Deposited: 02 Dec 2016 14:57
Last Modified: 02 Feb 2019 15:55
URI: http://d-scholarship.pitt.edu/id/eprint/29781

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