Enhanced Optic Nerve Expansion and Altered Ultrastructure of Elastic Fibers Induced by Lysyl Oxidase Inhibition in a Mouse Model of Marfan Syndrome

Abstract

Two major constituents of exfoliation material (XFM), fibrillin- 1 and lysyl oxidase-like 1 (encoded by FBN1 and LOXL1) are implicated in exfoliation glaucoma (XFG), yet their individual contributions to ocular phenotype are minor. To test the hypothesis that a combination of FBN1 mutation and LOXL1 deficiency exacerbates ocular phenotypes, pan-LOX inhibitor, β-aminopropionitrile (BAPN) was used to treat adult wild-type (wt) and Fbn1C1041G/+ mice for 8 weeks and their eyes were examined. Although intraocular pressure was not changed and XFM not detected in the eyes, BAPN treatment worsened optic nerve and axon expansion in Fbn1C1041G/+ mice, an early sign of axonal damage in rodent models of glaucoma. Disruption of elastic fibers was only detected in Fbn1C1041G/+ mice, which increased with BAPN treatment, revealed by histological and immunohistochemical staining of the optic nerve pia mater. Transmission electron microscopy showed that Fbn1C1041G/+ mice had fewer microfibrils, smaller elastin cores and lower density of elastic fibers as compared to wt mice in control groups. BAPN treatment led to elastin core expansion in both wt and Fbn1C1041G/+ mice, but an increase in the density of elastic fiber was confined to Fbn1C1041G/+ mice. LOX inhibition had a stronger effect on optic nerve and elastic fiber parameters in the context of Fbn1 mutation, indicating Marfan mouse model with LOX inhibition warrants further investigation for XFG pathogenesis.