HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marin-Castaño, M. E. Articles by Cousins, S. W. Search for Related Content PubMed PubMed Citation Articles by Marin-Castaño, M. E. Articles by Cousins, S. W.

Regulation of Estrogen Receptors and MMP-2 Expression by Estrogens in Human Retinal Pigment Epithelium

¹From the Bascom Palmer Eye Institute, Department of Ophthalmology, and the ²Vascular Biology Institute, University of Miami School of Medicine, Miami, Florida; and the ³Laboratory of Immunology, National Eye Institute, Bethesda, Maryland.

PURPOSE. Age-related macular degeneration (ARMD) is characterized by progressive thickening and accumulation of various lipid-rich extracellular matrix (ECM) deposits under the retinal pigment epithelium (RPE). ECM dysregulation probably contributes to the pathologic course of ARMD. By activating estrogen receptors (ERs), estrogens regulate the expression of genes relevant in the turnover of ECM, among them matrix metalloproteinase (MMP)-2. Estrogen deficiency may predispose to dysregulated synthesis and degradation of ECM, leading to accumulation of collagens and other proteins between the RPE and its basement membrane. The purposes in the current study were to confirm the expression of ERs in human RPE, to elucidate whether these ERs are functional, and to test whether 17ß-estradiol (E₂) regulates expression of ERs and MMP-2.

METHODS. Expression of ERs was examined in freshly isolated human RPE monolayer and in cultured human RPE cells, by using total RNA for RT-PCR and protein extracts for Western blot analysis. Supernatants were collected from freshly isolated human RPE and from cultured human RPE to assess MMP-2 activity by zymography and protein expression by Western blot. The transcriptional activity of ERs was studied in transfection experiments with an estrogen-responsive reporter construct. All these studies were preformed in the presence or absence of E₂ (10^-11 and 10^-7 M).

RESULTS. Human RPE isolated from female and male individuals expressed both ER subtypes and ß at the mRNA and protein levels. Treatment of cultured RPE cells with 10^-10 M E₂ increased expression of mRNA and protein of both receptor subtypes. E₂ (10^-10 M) also increased MMP-2 activity (2.2-fold) and protein expression (2.5-fold). In contrast, there was no change in ER levels and MMP-2 activity at higher E₂ concentrations (10^-8 M), compared with baseline. Preincubation of cells with 10^-7 M pyrrolidinedithiocarbamate (PDTC), an inhibitor of nuclear factor (NF)-B, abolished the increase in MMP-2 activity and protein expression induced by E₂ at 10^-10 M.

CONCLUSIONS. Both ER subtypes are expressed in RPE and regulated in a dose-dependent fashion by E₂. Estrogens similarly regulate MMP-2. This estrogen-induced effect is, at least in part, mediated through NF-B. These data support the hypothesis that estrogens may exert biological function in RPE through ERs and that estrogen deficiency or excess may cause dysregulation of molecules that influence the turnover of ECM in Bruch’s membrane associated with ARMD.

This article has been cited by other articles:

				R. L. Seitzman, V. B. Mahajan, C. Mangione, J. A. Cauley, K. E. Ensrud, K. L. Stone, S. R. Cummings, M. C. Hochberg, T. A. Hillier, J. S. Sinsheimer, et al. Estrogen Receptor Alpha and Matrix Metalloproteinase 2 Polymorphisms and Age-related Maculopathy in Older Women Am. J. Epidemiol., May 15, 2008; 167(10): 1217 - 1225. [Abstract] [Full Text] [PDF]

				D. Feskanich, E. Cho, D. A. Schaumberg, G. A. Colditz, and S. E. Hankinson Menopausal and Reproductive Factors and Risk of Age-Related Macular Degeneration Arch Ophthalmol, April 1, 2008; 126(4): 519 - 524. [Abstract] [Full Text] [PDF]

				O. Alcazar, S. W. Cousins, and M. E. Marin-Castano MMP-14 and TIMP-2 Overexpression Protects against Hydroquinone-Induced Oxidant Injury in RPE: Implications for Extracellular Matrix Turnover Invest. Ophthalmol. Vis. Sci., December 1, 2007; 48(12): 5662 - 5670. [Abstract] [Full Text] [PDF]

				S. S. Boekhoorn, J. R. Vingerling, A. G. Uitterlinden, J. B. J. Van Meurs, C. M. van Duijn, H. A. P. Pols, A. Hofman, and P. T. V. M. de Jong Estrogen Receptor {alpha} Gene Polymorphisms Associated with Incident Aging Macula Disorder Invest. Ophthalmol. Vis. Sci., March 1, 2007; 48(3): 1012 - 1017. [Abstract] [Full Text] [PDF]

				T. Suzuki, M. Mandai, M. Akimoto, N. Yoshimura, and M. Takahashi The Simultaneous Treatment of MMP-2 Stimulants in Retinal Transplantation Enhances Grafted Cell Migration into the Host Retina Stem Cells, November 1, 2006; 24(11): 2406 - 2411. [Abstract] [Full Text] [PDF]

				S. Elliot, P. Catanuto, W. Stetler-Stevenson, and S. W. Cousins Retinal Pigment Epithelium Protection from Oxidant-Mediated Loss of MMP-2 Activation Requires Both MMP-14 and TIMP-2. Invest. Ophthalmol. Vis. Sci., April 1, 2006; 47(4): 1696 - 1702. [Abstract] [Full Text] [PDF]

				M. E. Marin-Castano, K. G. Csaky, and S. W. Cousins Nonlethal Oxidant Injury to Human Retinal Pigment Epithelium Cells Causes Cell Membrane Blebbing but Decreased MMP-2 Activity Invest. Ophthalmol. Vis. Sci., September 1, 2005; 46(9): 3331 - 3340. [Abstract] [Full Text] [PDF]

				T. M. Doherty, L. A. Fitzpatrick, D. Inoue, J.-H. Qiao, M. C. Fishbein, R. C. Detrano, P. K. Shah, and T. B. Rajavashisth Molecular, Endocrine, and Genetic Mechanisms of Arterial Calcification Endocr. Rev., August 1, 2004; 25(4): 629 - 672. [Abstract] [Full Text] [PDF]

				V. Bourdeau, J. Deschenes, R. Metivier, Y. Nagai, D. Nguyen, N. Bretschneider, F. Gannon, J. H. White, and S. Mader Genome-Wide Identification of High-Affinity Estrogen Response Elements in Human and Mouse Mol. Endocrinol., June 1, 2004; 18(6): 1411 - 1427. [Abstract] [Full Text] [PDF]

				J. A. Smith, S. Vitale, G. F. Reed, S. A. Grieshaber, L. A. Goodman, V. H. Vanderhoof, K. A. Calis, and L. M. Nelson Dry Eye Signs and Symptoms in Women With Premature Ovarian Failure Arch Ophthalmol, February 1, 2004; 122(2): 151 - 156. [Abstract] [Full Text] [PDF]

				I. J. Suner, D. G. Espinosa-Heidmann, M. E. Marin-Castano, E. P. Hernandez, S. Pereira-Simon, and S. W. Cousins Nicotine Increases Size and Severity of Experimental Choroidal Neovascularization Invest. Ophthalmol. Vis. Sci., January 1, 2004; 45(1): 311 - 317. [Abstract] [Full Text] [PDF]

				K. A. Young and R. L. Stouffer Gonadotropin and Steroid Regulation of Matrix Metalloproteinases and Their Endogenous Tissue Inhibitors in the Developed Corpus Luteum of the Rhesus Monkey During the Menstrual Cycle Biol Reprod, January 1, 2004; 70(1): 244 - 252. [Abstract] [Full Text] [PDF]

				J. Blackburn, E. E. Tarttelin, C. Y. Gregory-Evans, M. Moosajee, and K. Gregory-Evans Transcriptional Regulation and Expression of the Dominant Drusen Gene FBLN3 (EFEMP1) in Mammalian Retina Invest. Ophthalmol. Vis. Sci., November 1, 2003; 44(11): 4613 - 4621. [Abstract] [Full Text] [PDF]

				S. W. Cousins, M. E. Marin-Castano, D. G. Espinosa-Heidmann, A. Alexandridou, L. Striker, and S. Elliot Female Gender, Estrogen Loss, and Sub-RPE Deposit Formation in Aged Mice Invest. Ophthalmol. Vis. Sci., March 1, 2003; 44(3): 1221 - 1229. [Abstract] [Full Text] [PDF]