Estrogen receptor beta protects against in vivo injury in RPE cells.
Epidemiological data suggest that estrogen deficiency in postmenopausal women may contribute to the severity of AMD. We discovered that 17beta-estradiol (E2) was a crucial regulator of the severity of extracellular matrix turnover (ECM) dysregulation both in vivo and in vitro. We also found in vitro that the presence of estrogen receptor (ER)beta regulates MMP-2 activity. Therefore in an attempt to delineate the role of the ER subtypes, female estrogen receptor knockout (ERKO) mice were fed a high-fat diet, and the eyes were exposed to seven 5-second doses of nonphototoxic levels of blue-green light over 2 weeks. Three months after cessation of blue light treatment, transmission electron microscopy was performed to assess severity of deposits, Bruchs membrane changes, and choriocapillaris endothelial morphology. We found that changes in the trimolecular complex of pro-MMP-2, MMP-14 and TIMP-2 correlated with increased Bruch's membrane thickening or sub-retinal deposit formation (basal laminar deposits) in ERKObeta mice. In addition RPE isolated from ERKObeta mice had an increase in expression of total collagen and a decrease in MMP-2 activity. Finally we found that ERK an intermediate signaling molecule in the MMP pathway was activated in RPE isolated from ERKObeta mice. These data suggest that mice which lack ERbeta are more susceptible to in vivo injury associated with environmental light and high fat diet.
Sex and Gender Differences in Health and Disease, Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. selliot@med.miami.edu
Sharon J
SJ
Elliot
Paola
P
Catanuto
Diego G
DG
Espinosa-Heidmann
Pedro
P
Fernandez
Eleut
E
Hernandez
Peter
P
Saloupis
Kenneth
K
Korach
Michael
M
Karl
Scott W
SW
Cousins
D000818:Animals; D015153:Blotting, Western; D016570:Bruch Membrane / Q000378:metabolism / Q000648:ultrastructure; D018929:Cell Culture Techniques; D003094:Collagen / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D047629:Estrogen Receptor beta / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism* / Q000648:ultrastructure; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D017403:In Situ Hybridization; D008027:Light; D008268:Macular Degeneration / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000648:ultrastructure; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D004041:Dietary Fats; D047629:Estrogen Receptor beta; C507096:Mmp14 protein, mouse; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D048049:Extracellular Signal-Regulated MAP Kinases; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D053511:Matrix Metalloproteinase 14