Potential Role of BMP6-induced Iron Dysregulation in Age-Related Macular Degeneration Suggested by Analysis of Mouse Models and Post Mortem Human Retinas

Abstract

Purpose: : Iron homeostasis is important for retinal health as excess iron leads to oxidative stress and retinal degeneration. Iron build-up may contribute to the pathogenesis of age-related macular degeneration (AMD). The mechanisms leading to this retinal iron accumulation are poorly understood. As bone morphogenic protein 6 (BMP6) is a major regulator of systemic iron, we tested the potential role of BMP6 in retinal iron regulation and in AMD.

Methods: : Retinas of Bmp6-/- mice were analyzed by histology, autofluorescence spectral analysis, quantitative iron detection, Perls’ iron stain, and immunolabeling. Mechanisms of retinal iron regulation were evaluated through qPCR following intravitreal BMP6 injection in mice. Cultured RPE cells were used to assess BMP6 expression following oxidative stress and iron load. Post mortem eyes from patients with AMD were analyzed by immunolabeling and Western analysis.

Results: : We demonstrate that BMP6 is expressed by RPE. In cultured RPE cells, it was downregulated by oxidative stress and upregulated by iron. Intraocular BMP6 protein injection resulted in upregulation of retinal hepcidin which led to decreased labile iron. BMP6 is necessary for normal retinal iron homeostasis, as Bmp6-/- mice had age-dependent retinal iron accumulation and degeneration. Post mortem eyes from patients with AMD had altered BMP6 levels.

Conclusions: : These results suggest that BMP6 regulates retinal iron homeostasis by upregulating hepcidin. Since oxidative stress is associated with AMD and downregulates BMP6 in cultured RPE cells, the diminished BMP6 levels observed in RPE cells in early AMD eyes may contribute to iron build-up in AMD. This may propagate a vicious cycle of oxidative stress and iron accumulation. Future studies on BMP6 regulatory mechanisms as well as the testing of iron chelators in Bmp6-/- mice may suggest novel therapeutic avenues for patients with AMD. Oxidative stress-induced downregulation of BMP6 could also contribute to the pathogenesis of other disorders involving iron toxicity, including hemochromatosis and neurodegenerative diseases.

Keywords: age-related macular degeneration • oxidation/oxidative or free radical damage