[New pathogenetic insights into pseudoexfoliation syndrome/glaucoma. Therapeutically relevant?].
Pseudoexfoliation (PEX) syndrome is a genetically determined, generalized disease of the extracellular matrix leading to the progressive deposition of an abnormal fibrillar material in various intraocular and extraocular tissues including the trabecular meshwork. It thus represents the most common identifiable cause of open-angle glaucoma and a leading cause of blindness worldwide. The PEX-specific fibrotic matrix process, a stress-induced elastosis, is characterized by an excessive production and abnormal cross-linking of elastic microfibrils into fibrillar PEX aggregates. Co-modulating factors triggering this fibrotic process include elevated concentrations of fibrogenic growth factors, such as TGF-β1, reduced activity of proteolytic enzymes, subtle inflammatory processes and various external stress factors, such as oxidative stress. Genetic studies identified a highly significant association between several polymorphisms in the LOXL1 (lysyl oxidase-like 1) gene with both PEX syndrome and PEX glaucoma. As these LOXL1 risk variants were found to occur in almost 100% of PEX patients throughout all geographical populations worldwide, LOXL1 appears to represent a principal risk factor for manifestation of the PEX phenotype. LOXL1 is a pivotal cross-linking enzyme in extracellular matrix metabolism and seems to be specifically required for elastic fiber formation and stabilization. The available data suggest that LOXL1 enzyme function and expression are dysregulated in PEX tissues and thereby play a central role in glaucoma development. On the one hand, increased expression of LOXL1 and elastic fiber components contributes to the formation of abnormally cross-linked PEX aggregates in the outflow pathways leading to increased outflow resistance and intraocular pressure. On the other hand, reduced expression and inadequate tissue levels of LOXL1 may lead to degenerative tissue alterations, particularly in the lamina cribrosa adversely affecting the biomechanical properties of this critical tissue. This PEX-specific elastinopathy of the lamina cribrosa rendering PEX eyes more vulnerable to pressure-induced optic nerve damage may constitute an independent risk factor for glaucoma development. The findings may have direct consequences for the clinical management of PEX patients underlining the need for an exact diagnosis, a strict IOP-reducing therapy and a close and regular follow-up.
Augenklinik, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen. ursula.schloetzer-schrehardt@uk-erlangen.de
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D015897:Comorbidity; D004547:Elastic Tissue / Q000473:pathology / Q000502:physiology; D017889:Exfoliation Syndrome / Q000235:genetics* / Q000503:physiopathology* / Q000628:therapy; D005109:Extracellular Matrix / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D006068:Gonioscopy; D006801:Humans; D007429:Intraocular Pressure / Q000235:genetics / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000502:physiology; D008855:Microscopy, Electron, Scanning; D008856:Microscopy, Fluorescence; D009900:Optic Nerve / Q000473:pathology / Q000503:physiopathology; D018384:Oxidative Stress / Q000502:physiology; D012307:Risk Factors; D051127:Scavenger Receptors, Class E / Q000235:genetics; D019714:Tissue Inhibitor of Metalloproteinases / Q000502:physiology; D014129:Trabecular Meshwork / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000502:physiology
C495137:OLR1 protein, human; D051127:Scavenger Receptors, Class E; D019714:Tissue Inhibitor of Metalloproteinases; D053773:Transforming Growth Factor beta1; D020782:Matrix Metalloproteinases