Abstract
Eyes with age-related macular degeneration (AMD) demonstrate accumulation of specific deposits and extracellular matrix (ECM) molecules under the retinal pigment epithelium (RPE). AMD is about two times more prevalent in aging postmenopausal women. Therefore we studied whether 17β-estradiol (E2) modulates the expression and activity of the trimolecular complex (MMP-2, TIMP-2 and MMP-14), molecules which are of major importance for ECM turnover in RPE. We used cell lines isolated from estrogen receptor knockout mice (ERKO) to determine which ER (estrogen receptor) subtype was important for ECM regulation in RPE cells. We found that mouse RPE sheets had higher baseline MMP-2 activity in the presence of ERβ. This correlated with higher MMP-2 activity in RPE cell lines isolated from ERKOα mice. Exposure to E2 increased MMP-2 activity in mouse RPE cell lines. In addition E2 increased transcriptional activation of the MMP-2 promoter through a functional Sp1 site which required the presence of ERβ, but not ERα. E2 also maintained levels of pro MMP-2, and MMP-14 and TIMP-2 activity after oxidant injury. Since the direct effects of E2 on MMP-2 transcriptional activation and the regulation of the trimolecular complex after oxidant-induced injury requires ERβ, this receptor subtype may have a role as a potential therapeutic target to prevent changes in activation of MMP-2.
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