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Ursula Schlotzer-Schrehardt, Christian M. Hammer, Carmen Hofmann-Rummelt, Friedrich E. Kruse, Gottfried O. Naumann, Matthias Zenkel; Sex-specific Differences in Expression and Regulation of Structural Proteins in the Lamina Cribrosa of Pseudoexfoliation Eyes. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5324.
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© ARVO (1962-2015); The Authors (2016-present)
Although pseudoexfoliation (PEX) syndrome is more prevalent in elderly women than in men, male gender is a risk factor for the development of PEX glaucoma with a nearly 2:1 male:female ratio in most studies. To identify mechanisms responsible for this gender difference, we comparatively analyzed expression of major structural proteins determining biomechanical properties in male and female lamina cribrosa (LC) specimens and optic nerve head (ONH) astrocytes obtained from PEX and control eyes.
Protein and mRNA expression of structural proteins (elastin, fibrillin-1, fibulin-4, collagen types I,III,IV), cross-linking enzymes (LOX, LOXL1), and sex hormone receptors (ER, PR, AR) were assessed by real-time PCR and immunohistochemistry in LC specimens obtained from 25 donor eyes with early and late PEX syndrome (11 male, 14 female) and 25 age-matched normal eyes (14 male, 11 female) and in cultivated human ONH astrocytes after incubation with 1-50 nM 17ß-estradiol, progesterone, or testosterone for 48 hours. Elastin and collagen content in LC tissue was quantitatively analyzed using histochemical stainings and image analysis software.
LC tissue of all PEX eyes revealed a significant site-specific downregulation of LOXL1, elastin, fibrillin-1, and fibulin-4 mRNA and protein (about 2-fold; p<0.001), whereas LOX, collagen, and hormone receptor expression was not different from controls. In the PEX but not in the control group, expression levels of LOXL1 and elastic proteins were significantly higher (about 2-fold; p<0.01) in LC tissue of female patients than that of male patients in both early and late stages of PEX. As compared to controls, the decrease in volume percent elastin was less pronounced in LC of female patients (about 15%) than in male patients (about 23%) with PEX. Sex steroids differentially regulated protein expression in cultivated ONH astrocytes with female hormones increasing expression of LOXL1 and elastic fiber components (about 3- to 6-fold; p<0.001) relative to controls.
Sex-specific differences in expression of major structural proteins in LC tissue of PEX eyes, which may be due to differential regulatory effects of sex hormones, could explain the gender disparity in predisposition to PEX-associated glaucoma.
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