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17?-estradiol Induces MMP-9 and MMP-13 in TMJ Fibrochondrocytes via Estrogen Receptor ?.

ABSTRACT: Temporomandibular joint (TMJ) disorders, including degenerative TMJ disease, occur primarily in women of reproductive age. Previous studies showed elevated estrogen levels in subjects with TMJ disorders relative to controls and the presence of estrogen receptors ? and ? (ER? and ER?) in TMJ fibrocartilage. Additionally, estrogen-induced overexpression of specific matrix metalloproteinases (MMPs), including MMP-9 and MMP-13, in TMJ fibrocartilage is accompanied by loss of extracellular matrices. However, the contribution of ER? and ER? in estrogen-mediated induction of MMP-9 and MMP-13 and the signaling cascade leading to the upregulation of these MMPs have not been elucidated. Here, we show that specific siRNAs and selective ER antagonists effectively block ER? or ER? expression in primary mouse TMJ fibrochondrocytes, but that only blockage of ER? suppresses MMP-9 and MMP-13 levels induced by 17?-estradiol (E2). Overexpression of ER? but not ER? enhances E2-induced MMP-9. Using the same loss-of-function and gain-of-function approaches, we demonstrate that E2 stimulates ERK activation through ER? and that inhibition of ERK phosphorylation reduces E2-induced MMP-9. Furthermore, we reveal that E2 promotes NF-?B and ELK-1 activation through ER?/ERK signaling and that knockdown of either one decreases the respective activity of these signaling mediators and MMP-9 expression induced by E2, indicating that both contribute to E2/ER?/ERK-mediated MMP-9 upregulation. This is supported by findings in which mutated binding sites of either NF-?B or ELK-1 in the MMP-9 promoter lead to a significant reduction of E2-stimulated promoter activity. Our findings provide novel molecular mechanisms for the understanding of E2-mediated upregulation of MMPs, having implications to pathophysiologic TMJ cartilage matrix turnover that may yield therapeutic intervention targets for TMJ disorders.

SUBMITTER: Ahmad N

PROVIDER: S-EPMC6055253 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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17β-estradiol Induces MMP-9 and MMP-13 in TMJ Fibrochondrocytes via Estrogen Receptor α.

Ahmad N N Chen S S Wang W W Kapila S S

Journal of dental research 20180405 9

Temporomandibular joint (TMJ) disorders, including degenerative TMJ disease, occur primarily in women of reproductive age. Previous studies showed elevated estrogen levels in subjects with TMJ disorders relative to controls and the presence of estrogen receptors α and β (ERα and ERβ) in TMJ fibrocartilage. Additionally, estrogen-induced overexpression of specific matrix metalloproteinases (MMPs), including MMP-9 and MMP-13, in TMJ fibrocartilage is accompanied by loss of extracellular matrices. ...[more]

PMID: 29621430

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Project description:Rationale17β-Estradiol (E2) attenuates hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension (HPH) through an unknown mechanism that may involve estrogen receptors (ER) or E2 conversion to catecholestradiols and methoxyestradiols with previously unrecognized effects on cardiopulmonary vascular remodeling.ObjectivesTo determine the mechanism by which E2 exerts protective effects in HPH.MethodsMale rats were exposed to hypobaric hypoxia while treated with E2 (75 μg/kg/d) or vehicle. Subgroups were cotreated with pharmacologic ER-antagonist or with inhibitors of E2-metabolite conversion. Complementary studies were performed in rats cotreated with selective ERα- or ERβ-antagonist. Hemodynamic and pulmonary artery (PA) and right ventricular (RV) remodeling parameters, including cell proliferation, cell cycle, and autophagy, were measured in vivo and in cultured primary rat PA endothelial cells.Measurements and main resultsE2 significantly attenuated HPH endpoints. Hypoxia increased ERβ but not ERα lung vascular expression. Co-treatment with nonselective ER inhibitor or ERα-specific antagonist rendered hypoxic animals resistant to the beneficial effects of E2 on cardiopulmonary hemodynamics, whereas ERα- and ERβ-specific antagonists opposed the remodeling effects of E2. In contrast, inhibition of E2-metabolite conversion did not abolish E2 protection. E2-treated hypoxic animals exhibited reduced ERK1/2 activation and increased expression of cell-cycle inhibitor p27(Kip1) in lungs and RV, with up-regulation of lung autophagy. E2-induced signaling was recapitulated in hypoxic but not normoxic endothelial cells, and was associated with decreased vascular endothelial growth factor secretion and cell proliferation.ConclusionsE2 attenuates hemodynamic and remodeling parameters in HPH in an ER-dependent manner, through direct antiproliferative mechanisms on vascular cells, which may provide novel nonhormonal therapeutic targets for HPH.

Dataset Information

17?-estradiol Induces MMP-9 and MMP-13 in TMJ Fibrochondrocytes via Estrogen Receptor ?.

Publications

17β-estradiol Induces MMP-9 and MMP-13 in TMJ Fibrochondrocytes via Estrogen Receptor α.

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