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

• Published in: The American journal of pathology Vol. 194; no. 7; pp. 1317 - 1328
• Main Authors: Wu, Hang-Jing, Krystofiak, Evan, Kuchtey, John, Kuchtey, Rachel W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2024; American Society for Investigative Pathology
• Subjects: Adipokines; Amino Acid Oxidoreductases - antagonists & inhibitors; Amino Acid Oxidoreductases - genetics; Amino Acid Oxidoreductases - metabolism; Aminopropionitrile - pharmacology; Animals; Disease Models, Animal; Elastic Tissue - metabolism; Elastic Tissue - pathology; Elastic Tissue - ultrastructure; Fibrillin-1 - genetics; Fibrillins - metabolism; Glaucoma - pathology; Intraocular Pressure; Marfan Syndrome - complications; Marfan Syndrome - pathology; Mice; Mice, Inbred C57BL; Microfilament Proteins - metabolism; Optic Nerve - drug effects; Optic Nerve - pathology; Optic Nerve - ultrastructure; Protein-Lysine 6-Oxidase - antagonists & inhibitors; Protein-Lysine 6-Oxidase - metabolism; Regular
• ISSN: 0002-9440; 1525-2191; 1525-2191
• DOI: 10.1016/j.ajpath.2024.03.002

Two major constituents of exfoliation material, fibrillin-1 and lysyl oxidase-like 1 (encoded by FBN1 and LOXL1), are implicated in exfoliation glaucoma, 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, the pan–lysyl oxidase inhibitor β-aminopropionitrile (BAPN) was used to treat adult wild-type (WT) mice and mice heterozygous for a missense mutation in Fbn1 (Fbn1C1041G/+) for 8 weeks and their eyes were examined. Although intraocular pressure did not change and exfoliation material was 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 detected only in Fbn1C1041G/+ mice, which increased with BAPN treatment, as shown by histologic and immunohistochemical staining of the optic nerve pia mater. Transmission electron microscopy showed that Fbn1C1041G/+ mice had fewer microfibrils, smaller elastin cores, and a lower density of elastic fibers compared with 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 the Marfan mouse model with LOX inhibition warrants further investigation for exfoliation glaucoma pathogenesis.