Genetic background determines severity of Loxl1-mediated systemic and ocular elastosis in mice

• Published in: Disease models & mechanisms Vol. 16; no. 11
• Main Authors: Suarez, Maria F, Schmitt, Heather M, Kuhn, Megan S, Watkins, TeddiJo, Hake, Kristyn M, Weisz, Tara, Flynn, 3rd, Edward J, Elliott, Michael H, Hauser, Michael A, Stamer, W Daniel
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists 01-11-2023
• Subjects: Amino Acid Oxidoreductases - genetics; Amino Acid Oxidoreductases - metabolism; Animals; Eye - metabolism; Female; Genetic Background; glaucoma; Humans; lysyl oxidase; mechanical stress; Mice; Mice, Inbred C57BL; Pelvic Organ Prolapse; Polymorphism, Single Nucleotide; pseudoexfoliation syndrome; trabecular meshwork; Glaucoma; Pseudoexfoliation syndrome; Trabecular meshwork; Lysyl oxidase; Mechanical stress
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.050392

Pseudoexfoliation syndrome (PEX) is a systemic, age-related disorder characterized by elastosis and extracellular matrix deposits. Its most significant ocular manifestation is an aggressive form of glaucoma associated with variants in the gene encoding lysyl oxidase-like 1 (LOXL1). Depending upon the population, variants in LOXL1 can impart risk or protection for PEX, suggesting the importance of genetic context. As LOXL1 protein levels are lower and the degree of elastosis is higher in people with PEX, we studied Loxl1-deficient mice on three different genetic backgrounds: C57BL/6 (BL/6), 129S×C57BL/6 (50/50) and 129S. Early onset and high prevalence of spontaneous pelvic organ prolapse in BL/6 Loxl1-/- mice necessitated the study of mice that were <2 months old. Similar to pelvic organ prolapse, most elastosis endpoints were the most severe in BL/6 Loxl1-/- mice, including skin laxity, pulmonary tropoelastin accumulation, expansion of Schlemm's canal and dilation of intrascleral veins. Interestingly, intraocular pressure was elevated in 50/50 Loxl1-/- mice, depressed in BL/6 Loxl1-/- mice and unchanged in 129S Loxl1-/- mice compared to that of control littermates. Overall, the 129S background was protective against most elastosis phenotypes studied. Thus, repair of elastin-containing tissues is impacted by the abundance of LOXL1 and genetic context in young animals.