TY - JOUR
T1 - Subtype specific estrogen receptor action protects against changes in MMP-2 activation in mouse retinal pigmented epithelial cells
AU - Elliot, Sharon
AU - Catanuto, Paola
AU - Fernandez, Pedro
AU - Espinosa-Heidmann, Diego
AU - Karl, Michael
AU - Korach, Kenneth
AU - Cousins, Scott W.
N1 - Funding Information:
This work was supported in part by National Institutes of Health, National Eye Institute Grant RO1 EY14477-04 (SJE MK, and SWC).
PY - 2008/4
Y1 - 2008/4
N2 - 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.
AB - 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.
KW - age related macular degeneration
KW - estrogen
KW - estrogen receptor
KW - extracellular matrix
KW - matrix metalloproteinases
KW - tissue inhibitors of metalloproteinases
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U2 - 10.1016/j.exer.2008.01.010
DO - 10.1016/j.exer.2008.01.010
M3 - Article
C2 - 18313050
AN - SCOPUS:41049093223
SN - 0014-4835
VL - 86
SP - 653
EP - 660
JO - Experimental eye research
JF - Experimental eye research
IS - 4
ER -