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DG Espinosa, ME Marin, E Hernandez, KG Csaky, SW Cousins; Estrogen Depletion Decreases Matrix Metalloproteinase-2 Expression and Increases SubRPE Deposit Accumulation in Mice . Invest. Ophthalmol. Vis. Sci. 2002;43(13):698.
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Purpose: Post-menopausal women may be at risk for more severe age-related macular degeneration (AMD), and estrogen loss may contribute. We have shown that human RPE demonstrate a biphasic response to estrogen, upregulating MMP-2 in response to low physiological concentrations but downregulating in response to greater levels. We sought to determine the effect of estrogen depletion or supplementation on RPE MMP-2 and -9 expression in a mouse model of subRPE deposit formation. Methods: C57BL/6 mice, aged 36 weeks, underwent ovariectomy or sham operation, with or without estrogen replacement (17 ß-estradiol sustained release pellets) producing a wide range of blood estradiol levels. Three weeks after surgery, four mice per group were killed, and the RPE recovered for MMP-2 and -9 expression by zymography and RT-PCR. In the remaining mice, subRPE deposits were produced by feeding mice a high fat diet for five months with short term exposure to blue-green light. TEM was performed to quantify Bruch's membrane (BM) thickness and subRPE deposit severity using a semi-quantitative scoring system (15 points). Results: Compared to sham-operated controls, estrogen depletion resulted in marked decline of MMP-2 and -9 expression. The estrogen depleted group also demonstrated a corresponding increase in deposit severity (1.8±1.3 v. 4.9±3.6, p< 0.05) but no change in BM thickening. Low dose estrogen replacement increased MMP expression above baseline, but moderate or high dose estrogen replacement was associated with depressed MMP expression. High dose supplementation also failed to protect against deposit formation (4.9±3.2), but did result in marked thinning of BM (20.7±4.1 v 12.7±2.5). Conclusions: Estrogen loss resulted in decreased MMP expression associated with increased subRPE deposit formation. As in human RPE, a biphasic response to estrogen was observed. RPE-mediated dysregulated extracellular matrix turnover by age-related loss of estrogen or other circulating factors might contribute to deposit formation in AMD. However, in part because of the biphasic response, estrogen replacement therapy might not necessarily restore normal regulation nor protect from deposit formation.
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