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U. Schlotzer-Schrehardt, A. Krysta, T. Sasaki, A. Junemann, F. E. Kruse, G. O. H. Naumann, M. Zenkel; Interaction Between LOXL1 and Elastic Fiber Proteins in Fibrogenesis Associated With Pseudoexfoliation Syndrome. Invest. Ophthalmol. Vis. Sci. 2009;50(13):863.
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© ARVO (1962-2015); The Authors (2016-present)
Genetic variants in the lysyl oxidase-like 1 (LOXL1) gene, coding for a key enzyme in elastic fiber homeostasis, have been recently identified as strong genetic risk factor for both pseudoexfoliation (PEX) syndrome and glaucoma. Here we investigated the interaction of LOXL1 and elastic fiber proteins in PEX-associated fibrogenesis in ocular tissues and in vitro models.
Fifteen donor eyes with PEX syndrome/glaucoma and 15 age-matched control eyes were used. mRNA expression of LOXL1 and elastic fiber components was analyzed using quantitative real-time PCR. Immunohistochemical analysis was performed on the light and electron microscopic level using antibodies against LOXL1 and various elastic fiber components. Matrix production was analyzed in human Tenon’s capsule fibroblasts from PEX and control patients using 2D- and 3D-culture models. The findings were correlated with the patients’ individual LOXL1 genotypes.
Quantitative RT-PCR showed significant upregulation of fibrillin-1, LTBP-1/2, fibulin-2/4/6, and tropoelastin in PEX anterior segment tissues in parallel with LOXL1, while expression of fibrillin-2/3, LTBP-4, fibulin-1/3/5, MAGP-1/2, emilin-1, and fibronectin appeared unchanged compared with controls. Accordingly, double immunolabelling showed perfect co-localization of LOXL1 with fibrillin-1, LTBP-2, fibulin-4/6, and tropoelastin within PEX fibrils on the light and electron microscopic level. Fibroblasts in 2D- and 3D-culture models were found to assemble fibrillin-1, fibulin-2/4/6, LTBP-2 and tropoelastin into microfibrillar networks accumulating focal LOXL1-positive fiber aggregates in cultures derived from PEX patients carrying the high-risk diplotype of LOXL1 gene variants. Coimmunoprecipitation demonstrated specific binding between LOXL1, fibrillin-1 and fibulin-4/6.
These data indicate that interaction between LOXL1 and elastic fiber components contributes to the formation of abnormal fiber aggregates characteristic of PEX syndrome and glaucoma. Targeting of LOXL1 might therefore open new approaches for specific treatment strategies in the future.
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