Changes in extracellular matrix cause RPE cells to make basal deposits and activate the alternative complement pathway

The design of efficient therapies for age-related macular degeneration (AMD) is limited by our understanding of the pathogenesis of basal deposits, which form between retinal pigment epithelium (RPE) and Bruch’s membrane (BrM) early in disease, and involve activation of the complement system. To investigate the roles of BrM, RPE and complement in AMD, we generated ARPE-19 cells with the p.R345W mutation inEFEMP1, which causes early-onset macular degeneration. The ARPE-19-EFEMP1R345W/R345Wcells make abnormal extracellular matrix (ECM) that binds active complement C3 and causes the formation of basal deposits by normal human fetal (hf)RPE cells. hfRPE cells grown on abnormal ECM or BrM explants from AMD donors show chronic activation of the alternative complement pathway by excessive deposition of C3b. This process is exacerbated by impaired ECM turnover via increased matrix metalloproteinase-2 (MMP-2) activity. Therapies that target ECM synthesis and turnover and activation of C3 could be effective for early AMD.