Subtype specific estrogen receptor action protects against changes in MMP-2 activation in mouse retinal pigmented epithelial cells

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 (E 2 ) 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 E 2 increased MMP-2 activity in mouse RPE cell lines. In addition E 2 increased transcriptional activation of the MMP-2 promoter through a functional Sp1 site which required the presence of ERβ, but not ERα. E 2 also maintained levels of pro MMP-2, and MMP-14 and TIMP-2 activity after oxidant injury. Since the direct effects of E 2 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.

17-β Estradiol Protects ARPE-19 Cells from Oxidative Stress through Estrogen Receptor-β

“…Previously, it had been demonstrated that ER␤ plays an important role in regulating extracellular matrix turnover during oxidant injury in RPE both in vitro and in vivo. 14,31 These observations indicate that ER␤ can protect RPE from oxidative stress through multiple mechanisms.…”

The estrogenic retina: The potential contribution to healthy aging and age-related neurodegenerative diseases of the retina

“…ERβ-dependent neuroprotection also arises against oxidative stress in RPE cells, used as a model to investigate RPE dysfunction in AMD [131]. After oxidant injury of RPE cell lines isolated from ERKO mice, E2 effects on extracellular matrix metalloproteinases are mediated by ERβ, but not ERα [124]. Still, genistein and GTx-822, selective ERβ agonists, respectively protect the retina against ischemia [132], and RPE cells from oxidative stress-induced apoptosis.…”

“…However, in both retina and RPE, the nature of their co-existence remains still elusive; whether they complement, diverge or work independently is currently unknown. It has been reported that only ERβ activate extracellular matrix molecules in isolated human RPE cell lines [123], and ERβ specifically prevents changes in MMP-2 activation in RPE cells of ERs knockout mice [124].…”

Emerging roles for nuclear receptors in the pathogenesis of age-related macular degeneration

“…Conversely, Ayalasomayajula et al [146] recently showed that the corticosteroid fluocinolone can inhibit VEGF expression in the human RPE cell line, ARPE19, in a GR-dependent manner. In vivo murine models of estrogen receptor beta (ERβ) knockout have been associated with altered murine matrix metalloprotease-2 activity, increased collagen production, and sub-RPE deposit formation as seen in human dry AMD [147, 148], yet ERβ mRNA is reportedly undetectable in in vitro RPE cell cultures and freshly isolated human RPE [149]. The PPAR gamma (γ) has consistently been observed in ARPE19 cells and often in primary RPE cell lines harvested from human donors [150] and can become activated following photoreceptor phagocytosis [151], yet it is unclear if this occurs in the eye, as disparate results have been reported regarding its expression in freshly isolated human RPE cells and human sections [149, 152].…”