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Research ArticleArticle

Estrogen Receptor β Is a Novel Therapeutic Target for Photoaging

Ken C. N. Chang, Yihe Wang, Inn Gyung Oh, Susan Jenkins, Leonard P. Freedman, Catherine C. Thompson, Jin Ho Chung and Sunil Nagpal
Molecular Pharmacology May 2010, 77 (5) 744-750; DOI: https://doi.org/10.1124/mol.109.062877
Ken C. N. Chang
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Yihe Wang
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Inn Gyung Oh
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Susan Jenkins
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Leonard P. Freedman
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Catherine C. Thompson
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Jin Ho Chung
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Sunil Nagpal
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Abstract

One of the many harmful factors faced by the skin is solar UV radiation, which damages skin by inducing chronic low-grade inflammation through increased expression of proinflammatory cytokines, metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2). Estrogen receptors (ERs) α and β are ligand-dependent transcription factors that are expressed in skin, and an ERβ agonist has previously shown efficacy in vivo in models of pain and inflammation. Because ERβ does not carry the breast and uterine proliferation liabilities of ERα, we decided to explore the possibility of using ERβ as a target for photoaging. We show that ERβ-selective compounds suppressed the expression of cytokines and MMPs in activated keratinocytes and fibroblast-based in vitro models of photoaging. Furthermore, in activated dermal fibroblasts, ERβ-selective compounds also inhibited COX-2. These activities of ERβ ligands in skin cells correlated with the expression levels of ERβ and showed reversal by treatment with a potent synthetic ER antagonist. Furthermore, the pharmacology of ERβ-selective compound was observed in wild-type but not in skin cells obtained from ERβ knockout mice. Finally, we demonstrate that a synthetic ERβ agonist inhibited UV-induced photodamage and skin wrinkle formation in a murine model of photoaging. Therefore, the potential of an ERβ ligand to regulate multiple pathways underlying the cause of photoaging suggests ERβ to be a novel therapeutic target for the prevention and treatment of photoaging.

Footnotes

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.062877.

  • ABBREVIATIONS:

    AP-1
    activator protein 1
    MMP
    metalloproteinase
    COX-2
    cyclooxygenase-2
    ER
    estrogen receptor
    NHEK
    normal human epidermal keratinocyte
    LBD
    ligand binding domain
    NHDF
    normal human dermal fibroblast
    NF-κB
    nuclear factor-κB
    TNFα
    tumor necrosis factor-α
    HET
    heterozygote
    KO
    knockout
    TLDA
    TaqMan Low Density Array
    RT-PCR
    reverse transcriptase-polymerase chain reaction
    IL
    interleukin
    MED
    minimal erythema dose
    PPT
    4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol
    LXR
    liver X receptor
    Mapk1
    mitogen-activated protein kinase 1 gene
    ICI 182,780
    fulvestrant.

    • Received December 4, 2009.
    • Accepted January 28, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (5)
Molecular Pharmacology
Vol. 77, Issue 5
1 May 2010
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Research ArticleArticle

Estrogen Receptor β Is a Novel Therapeutic Target for Photoaging

Ken C. N. Chang, Yihe Wang, Inn Gyung Oh, Susan Jenkins, Leonard P. Freedman, Catherine C. Thompson, Jin Ho Chung and Sunil Nagpal
Molecular Pharmacology May 1, 2010, 77 (5) 744-750; DOI: https://doi.org/10.1124/mol.109.062877

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Research ArticleArticle

Estrogen Receptor β Is a Novel Therapeutic Target for Photoaging

Ken C. N. Chang, Yihe Wang, Inn Gyung Oh, Susan Jenkins, Leonard P. Freedman, Catherine C. Thompson, Jin Ho Chung and Sunil Nagpal
Molecular Pharmacology May 1, 2010, 77 (5) 744-750; DOI: https://doi.org/10.1124/mol.109.062877
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