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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.
AuthorsMajda Hadziahmetovic, Ying Song, Natalie Wolkow, Jared Iacovelli, Leon Kautz, Marie-Paule Roth, Joshua L Dunaief
JournalThe American journal of pathology (Am J Pathol) Vol. 179 Issue 1 Pg. 335-48 (Jul 2011) ISSN: 1525-2191 [Electronic] United States
PMID21703414 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Bmp6 protein, mouse
  • Bone Morphogenetic Protein 6
  • RNA, Messenger
  • Iron
Topics
  • Animals
  • Blotting, Western
  • Bone Morphogenetic Protein 6 (physiology)
  • Cells, Cultured
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Iron (metabolism)
  • Iron Overload
  • Macular Degeneration (etiology, pathology)
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oxidative Stress
  • RNA, Messenger (genetics)
  • Retinal Degeneration
  • Retinal Pigment Epithelium (metabolism, pathology)
  • Reverse Transcriptase Polymerase Chain Reaction

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