Interactions Between Epidermal Growth Factor-Containing Fibulin-Like Extracellular Matrix Protein 1 and Tissue Inhibitor of Metalloproteinases-3 and Relevance to Age-Related Macular Degeneration.

Clinical Relevance: Age-related macular degeneration (AMD) remains the leading cause of irreversible blindness in Western populations, with no approved therapies for the dry form characterized by drusen accumulation and retinal pigment epithelium atrophy. This review examines extracellular matrix alterations in Bruch's membrane by comparing healthy aging, AMD pathogenesis, and Doyne Honeycomb Retinal Dystrophy-a monogenic disorder that serves as a surrogate model for AMD due to similar phenotypic manifestations. Methods: We focus on the critical interactions between epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1), matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases-3, and complement factors. We explore their roles in extracellular matrix homeostasis disruption. In healthy aging, oxidative stress and inefficient waste removal drive gradual matrix remodeling and low-grade inflammation. Age-related macular degeneration results from polygenic risk variants in complement and extracellular matrix genes, combined with environmental stressors, leading to accelerated matrix dysfunction and chronic complement activation. In Doyne Honeycomb Retinal Dystrophy, the EFEMP1 R345W mutation causes rapid disease progression through impaired protein secretion, abnormal matrix accumulation, and complement dysregulation. Results: Our analysis reveals that EFEMP1-tissue inhibitor of metalloproteinases-3 complexation may represent a critical threshold in drusen formation across both conditions, AMD and Doyne Honeycomb Retinal Dystrophy. Conclusion: While AMD pathogenesis unfolds over decades through cumulative insults, the EFEMP1 mutation compresses similar pathological changes into 30 to 40 years, suggesting this mutation acts as a major hazard for matrix homeostasis disruption. Understanding these shared mechanisms provides insights into therapeutic targets, including complement inhibition, MMP modulation, and EFEMP1-directed interventions. We propose continued investigation of Doyne Honeycomb Retinal Dystrophy as a valuable model for identifying AMD treatments. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.