title: Bmp6 regulates retinal iron homeostasis and has altered expression in age-related macular degeneration.
abstract: Iron-induced oxidative stress causes hereditary macular degeneration in patients with aceruloplasminemia. 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 up-regulated 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.
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Majda
authors.initials: M
authors.lastname: Hadziahmetovic
authors.forename: Ying
authors.initials: Y
authors.lastname: Song
authors.forename: Natalie
authors.initials: N
authors.lastname: Wolkow
authors.forename: Jared
authors.initials: J
authors.lastname: Iacovelli
authors.forename: Leon
authors.initials: L
authors.lastname: Kautz
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Roth
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Dunaief
mesh_terms: D000818:Animals; D015153:Blotting, Western; D055418:Bone Morphogenetic Protein 6 / Q000502:physiology*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload; D008268:Macular Degeneration / Q000209:etiology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics; D012162:Retinal Degeneration; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; D012333:RNA, Messenger; D007501:Iron