title: Regulation of lysyl oxidase-like 1 (LOXL1) and elastin-related genes by pathogenic factors associated with pseudoexfoliation syndrome.
abstract: OBJECTIVE
  Pseudoexfoliation (PEX) syndrome/glaucoma is a complex, late-onset disorder of the elastic fiber system. 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 analyze the effect of various PEX-associated pathogenic factors on the genotype-correlated expression of LOXL1 and elastin-related genes.
  
  
  METHODS
  Cultured human Tenon's capsule fibroblasts with high- and low-risk LOXL1 haplotypes were exposed to transforming growth factor (TGF)-β1, interleukin (IL)-6, homocysteine, oxidative stress, hypoxia, or ultraviolet (UV) radiation. Changes in the expression of LOXL1 and elastic constituents of PEX material and TGF-β1 were assessed by quantitative real-time PCR, Western blotting, immunohistochemistry, and electron microscopy.
  
  
  RESULTS
  Treatment of fibroblasts with TGF-β1, oxidative stress, UV light, and hypoxia induced a significant increase in expression levels of LOXL1 and elastic proteins, whereas the effect of IL-6 was limited to induction of elastic constituents. Immunohistochemistry and electron microscopy confirmed an upregulation of LOXL1 and elastic fiber proteins and their assembly into extracellular microfibrillar networks with focal aggregation of microfibrils into PEX-like fibrils on stimulation with TGF-β1 and oxidative stress. Basal and stimulated expression of LOXL1 mRNA and protein was slightly decreased in cells carrying the high-risk compared with the low-risk haplotype of LOXL1, but the differences between groups were statistically not significant.
  
  
  CONCLUSIONS
  The findings support the notion that both genetic and nongenetic fibrogenic factors, particularly TGF-β1 and oxidative stress, may cooperate in the stable accumulation of PEX aggregates.
authors.affiliation: Department of Ophthalmology, University of Erlangen-Nürnberg, Erlangen, Germany. matthias.zenkel@uk-erlangen.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Zenkel
authors.forename: Anita
authors.initials: A
authors.lastname: Krysta
authors.forename: Francesca
authors.initials: F
authors.lastname: Pasutto
authors.forename: Anselm
authors.initials: A
authors.lastname: Juenemann
authors.forename: Friedrich E
authors.initials: FE
authors.lastname: Kruse
authors.forename: Ursula
authors.initials: U
authors.lastname: Schlötzer-Schrehardt
mesh_terms: D000369:Aged, 80 and over; D000594:Amino Acid Oxidoreductases / Q000235:genetics*; D015153:Blotting, Western; D002478:Cells, Cultured; D004549:Elastin / Q000235:genetics*; D017889:Exfoliation Syndrome / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000502:physiology*; D005838:Genotype; D006710:Homocysteine / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D008854:Microscopy, Electron; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D058475:Tenon Capsule / Q000166:cytology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D006710:Homocysteine; D004549:Elastin; D006861:Hydrogen Peroxide; D000594:Amino Acid Oxidoreductases; C445313:LOXL1 protein, human