Expression and regulation of LOXL1 and elastin-related genes in eyes with exfoliation syndrome.

Exfoliation syndrome (XFS) is a complex, late-onset disorder of the elastic fiber system and the most common identifiable cause of open-angle glaucoma. Strong genetic risk is conferred by the lysyl oxidase-like 1 (LOXL1) gene, but additional comodulating factors are necessary for the manifestation of the disease. The aim of this study was to establish a comprehensive expression profile of LOXL1 and elastic proteins in XFS eyes and to analyze their regulation in an in vitro cell culture system. Eyes with XFS with and without glaucoma, and normal control eyes were analyzed for major elastic fiber components (elastin, fibrillin-1, fibulin-4), and lysyl oxidase (LOX) enzymes by real-time PCR, immunohistochemistry, and electron microscopy. Cultured human Tenon's capsule fibroblasts were exposed to transforming growth factor-β1, IL-6, homocysteine, oxidative stress, hypoxia, or ultraviolet radiation, and changes in the expression of LOXL1 and elastic components of XFS material were assessed by real-time PCR, immunohistochemistry, and Western blotting. LOXL1 expression in anterior eye tissues was significantly increased in early XFS stages but was decreased in advanced stages as compared with controls. LOXL1 was also found to be a major component of XFS material and to colocalize with elastin, fibrillin-1, and fibulin-4, which were upregulated in parallel to LOXL1. In contrast, in most posterior segment tissues, LOXL1 and elastic fiber proteins displayed no differential expression. Interestingly, lamina cribrosa specimens of early and late XFS stages without and with glaucoma revealed a selective downregulation of LOXL1 and elastic fiber components on the mRNA and protein level, which was associated with pronounced ultrastructural alterations of the laminar elastic fiber network in XFS eyes. Treatment of cultured cells with XFS-associated pathogenetic stimuli induced a significant increase in the expression of LOXL1 and elastic proteins and resulted in their assembly into XFS-like fibrils in vitro. The findings support the notion that both genetic and nongenetic factors may cooperate in the stable accumulation of XFS aggregates and provide evidence for a XFS-specific elastinopathy of the lamina cribrosa, possibly rendering XFS eyes more vulnerable to pressure-induced optic nerve damage and glaucoma development.