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T. Suzuki, D.A. Sullivan; Estrogen-induced Increase of Matrix Metalloproteinase mRNA Levels in Human Corneal Epithelial Cells . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1027.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:Investigators have shown that estrogen treatment of postmenopausal women is associated with a significant increase in the prevalence of dry eye syndromes. We hypothesize that this hormone effect may be due, at least in part, to an increased synthesis and secretion of matrix metalloproteinases (MMP) by the cornea. These corneal proteins have been implicated in the pathogenesis of ocular surface inflammation in dry eye, and their production is known to be increased by estrogens in other tissues. To begin to test our hypothesis, we sought to determine whether estrogen stimulates MMP gene expression in human corneal epithelial cells. Methods:Human corneal epithelial cells (gift from Santen Pharmaceutical, Japan) were cultured in serum-containing media until confluence, then switched to serum-free media (DMEM-ITS) for 48 hours. Following this time course, cells were cultured in DMEM-ITS containing vehicle, lipopolysaccharide (LPS, 10µg/ml, positive control), or 10 nM, 0.1 nM or 1.0 pM 17ß-estradiol. After 6 or 24 hours of hormone exposure, cells were harvested and processed for total RNA isolation, cDNA synthesis and the analysis of MMP mRNA levels by multiplex and real-time PCR methods. Results:Our results demonstrate that 17ß-estradiol increases the mRNA levels of MMPs 7 and 9 in human corneal epithelial cells, as compared to amounts in vehicle-treated controls. This hormone action, which was consistently observed in different experiments, occurred after 6 and/or 24 hours of treatment with all three concentrations of 17ß-estradiol. Preliminary studies also indicate that estrogen may influence the expression of MMP2 mRNA. For comparison, an up-regulation of MMP gene expression was found following cellular exposure to LPS. Conclusions: Our results show that 17ß-estradiol enhances the expression of MMP genes in human corneal epithelial cells. To extend this finding, we are currently examining whether 17ß-estradiol also promotes the translation and secretion of these MMPs. Overall, these observations are consistent with our hypothesis, and suggest that estrogen action may play a role in the etiology of ocular surface inflammation in dry eye. (Supported by NIH grant EY05612 and postdoctoral fellowship awards from Allergan, Japan, Bausch & Lomb and the Japan Eye Bank Association)
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