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Ursula Schlotzer-Schrehardt, Angelika Mössner, Carmen Rummelt, Friedrich E Kruse, Matthias Zenkel; Expression and regulation of LOXL1 and elastic proteins in the lamina cribrosa: effects of age and sex. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):6155.
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© ARVO (1962-2015); The Authors (2016-present)
The risk of glaucoma is known to increase with age involving potential differences in gender predilection. In order to identify age- and sex-specific risk factors for glaucoma, we analysed factors potentially influencing extracellular matrix stiffness and biomechanical properties, i.e. structural proteins, cross-linking enzymes, and proteolytic enzymes, in lamina cribrosa (LC) tissue in relation to age and sex.
Protein and mRNA expression of elastin, fibrillin-1, fibulin-4, fibulin-5, collagen types I and III, lysyl oxidases LOX and LOXL1-4, matrix metalloproteinases (MMP)-1,-2,-3,-7,-9,-10,-12,-14, and their tissue inhibitors (TIMP)-1-4 were assessed by quantitative real-time PCR and immunohistochemistry in LC specimens obtained from 45 normal donor eyes (22 female, 23 male) aged 27 to 94 years. Regulation of these proteins was studied in cultivated human optic nerve head (ONH) astrocytes after incubation with 17ß-estradiol, progesterone, or testosterone. Lysyl oxidase activity and desmosine cross-links were analysed by specific assays, and elastic fiber morphology was evaluated by light and electron microscopy.
LOXL1 was found to be the only lysyl oxidase isoform which was markedly expressed in LC tissue both on the mRNA and protein level in association with LC cells and elastic fibers. There was a significant decrease in expression levels of LOXL1 (-53%), elastin (-44%), fibrillin-1 (-37%), collagen I (-40%) collagen III (-71%) and TIMP-4 (-60%) with a concomitant increase in levels of MMP-2 (2-fold) and MMP-3 (13-fold) in LC tissue from young donors compared to old donors. However, expression levels correlated with age only in female but not in male specimens. Reduced expression levels were accompanied by a decline in LOXL1 activity and elastin-specific desmosine cross-links as well as structural alterations of elastic fibers. Sex steroids differentially regulated protein expression in ONH astrocytes with female hormones increasing expression of LOXL1 and elastin and decreasing expression of MMPs relative to controls.
Age- and sex-related changes in elastic fiber integrity, caused by decreased cross-linking and increased proteolytic activities, which may be partly due to differential regulatory effects of sex hormones, may adversely affect the biomechanical properties of the LC and may have a profound impact on glaucoma susceptibility.
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