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S. Elliot, P. Catanuto, D. Espinosa-Heidmann, P. Fernandez, K. Korach, S. W. Cousins; Estrogen Receptor ß Is Protective in vivo and in vitro Against Oxidant Induced ECM Dysregulation. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3030.
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Eyes with age-related macular degeneration (AMD) demonstrate accumulation of specific deposits and extracellular matrix (ECM) molecules under the retinal pigment epithelium (RPE). We have previously published that formation of subretinal deposits occurs in ovariectomized mice suggesting that estrogen plays an important role in the maintenance of normal extracellular matrix turnover. However the specific ER subtype responsible for this preservation was not addressed by these experiments.Therefore we utilized estrogen receptor knockout mice (ERKO) mice to determine which ER subtype was important for ECM regulation in the RPE.
All groups of mice were fed either a high fat diet and exposed to blue light or normal chow. At the time of sacrifice, specimens were obtained for TEM and RPE cells were isolated. Immunhistochemistry was performed for ZO1, and western analysis for RPE65 was performed. Zymography was performed for analysis of MMP-2 activity. RNA was collected and real-time RT PCR performed.
TEM revealed severe deposits and thickening of Bruch’s membrane in those mice lacking ERß (ERKOß) compared to mice lacking ERα or wildtype littermates. RPE cells isolated from all groups of mice retained their in vivo phenotype and expressed specific markers. In addition, RPE cells isolated from ERKOß mice, had lower levels of MMP-2 mRNA and activity compared to all other groups (Table I). MMP-14 mRNA expression was also decreased. Collagen type I mRNA was significantly increased.
It appears that estrogen receptor ß plays a role in protection against oxidant injury mediated-MMP-2 activity decrease and collagen increase. Therefore ERß may have a role as a potential therapeutic target to prevent early ECM dysregulation of AMD.All values were calculated based on ratios of target molecule/18s.
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