Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 179, Issue 1, Pages 335-348Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2011.03.033
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Funding
- NIH [R01EY015240]
- American Health Assistance Foundation
- Pennsylvania Lions Eye Research Foundation
- F.M. Kirby Foundation
- Paul and Evanina Bell Mackall Foundation Trust
- University of Pennsylvania Biomedical Imaging Core
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Iron-induced oxidative stress causes hereditary macular degeneration in patients with aceruloplastninemia. Similarly, retinal iron accumulation in age-related macular degeneration (AMD) may exacerbate the disease. The cause of retinal iron accumulation in AMD is poorly understood. Given that bone morphogenetic protein 6 (Bmp6) is a major regulator of systemic iron, we examined the role of Bmp6 in retinal iron regulation and in AMD pathogenesis. Bmp6 was detected in the retinal pigment epithelium (RPE), a major site of pathology in AMD. In cultured RPE cells, Bmp6 was down-regulated by oxidative stress and upregulated by iron. Intraocular Bmp6 protein injection in mice up-regulated retinal hepcidin, an iron regulatory hormone, and altered retinal labile iron levels. Bmp6(-/-) mice had age-dependent retinal iron accumulation and degeneration. Postmortem RPE from patients with early AMD exhibited decreased Bmp6 levels. Because oxidative stress is associated with AMD pathogenesis and down-regulates Bmp6 in cultured RPE cells, the diminished Bmp6 levels observed in RPE cells in early AMD may contribute to iron 'build-up in AMD. This may in turn propagate a vicious cycle of oxidative stress and iron accumulation, exacerbating AMD and other diseases with hereditary or acquired iron excess. (Am J Pathol 2011, 179:335-344. DOI: 10.1016/j.ajpath.2011.03.033)
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