Abstract
Background/aims:
Excess fibrosis may lead to chronic pain, scarring, and infertility as endometriosis develops and progresses. The pathogenesis of endometriosis has been linked to transforming growth factor-β (TGF-β), the most potent promoter of fibrosis.
Methods:
Levels of NR4A1 and P-NR4A1 protein in human endometrial and endometriotic tissue were assessed by western blotting and immunohistochemistry. The expression levels of fibrotic markers in stromal cells were evaluated by real-time PCR. The degree of fibrosis in mouse endometriotic lesions was detected by Masson trichrome and Sirius red staining.
Results:
The level of phosphorylated-NR4A1 was higher in ovarian endometriotic tissue than in normal endometrium, and long-term TGF-β1 stimulation phosphorylated NR4A1 in an AKT-dependent manner and then promoted the expression of fibrotic markers. Furthermore, inhibition of NR4A1 in stromal cells increased the TGF-β1-dependent elevated expression of fibrotic markers, and loss of NR4A1 stimulated fibrogenesis in mice with endometriosis. Additionally, Cytosporone B (Csn-B), an NR4A1 agonist, effectively decreased the TGF-β1-dependent elevated expression of fibrotic markers in vitro and significantly inhibited fibrogenesis in vivo.
Conclusion:
NR4A1 can regulate fibrosis in endometriosis and may serve as a new target for the treatment of endometriosis.
Keywords:
Csn-B; Endometrial stromal cells; Endometriosis; Fibrosis; Phosphorylation; TGF-β1/NR4A1.
© 2018 The Author(s). Published by S. Karger AG, Basel.
MeSH terms
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Adult
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Animals
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Cells, Cultured
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Collagen Type I / genetics
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Collagen Type I / metabolism
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Collagen Type I, alpha 1 Chain
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Connective Tissue Growth Factor / genetics
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Connective Tissue Growth Factor / metabolism
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Disease Models, Animal
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Endometriosis / metabolism
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Endometriosis / pathology*
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Endometrium / cytology
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Endometrium / drug effects
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Endometrium / metabolism
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Endometrium / pathology
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Female
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Fibronectins / genetics
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Fibronectins / metabolism
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Fibrosis
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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Mice
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Mice, Nude
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Microscopy, Fluorescence
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Nuclear Receptor Subfamily 4, Group A, Member 1 / agonists
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Nuclear Receptor Subfamily 4, Group A, Member 1 / antagonists & inhibitors
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Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
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Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
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Phenylacetates / pharmacology
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Phosphorylation / drug effects
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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RNA Interference
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RNA, Small Interfering / metabolism
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Stromal Cells / cytology
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Stromal Cells / drug effects
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Stromal Cells / metabolism
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Transforming Growth Factor beta / pharmacology
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Transplantation, Heterologous
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Up-Regulation / drug effects
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Young Adult
Substances
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CCN2 protein, human
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Collagen Type I
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Collagen Type I, alpha 1 Chain
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Fibronectins
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Heterocyclic Compounds, 3-Ring
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MK 2206
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NR4A1 protein, human
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Phenylacetates
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RNA, Small Interfering
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Transforming Growth Factor beta
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cytosporone B
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Connective Tissue Growth Factor
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Proto-Oncogene Proteins c-akt