F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Am J Pathol. 2011 Jul;179(1):335-48. doi: 10.1016/j.ajpath.2011.03.033. Epub 2011 May 3.
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.
铁诱导的氧化应激导致铜蓝蛋白缺乏症患者发生遗传性黄斑变性。同样，年龄相关性黄斑变性（AMD）中的视网膜铁积累可能会使疾病恶化。AMD 中视网膜铁积累的原因尚不清楚。鉴于骨形态发生蛋白 6（Bmp6）是系统性铁的主要调节剂，我们研究了 Bmp6 在视网膜铁调节和 AMD 发病机制中的作用。Bmp6 在视网膜色素上皮（RPE）中被检测到，RPE 是 AMD 的主要病变部位。在培养的 RPE 细胞中，Bmp6 被氧化应激下调，被铁上调。在小鼠中眼内注射 Bmp6 蛋白可上调视网膜铁调节激素铁调素，并改变视网膜不稳定铁水平。Bmp6（-/-）小鼠出现年龄依赖性视网膜铁积累和变性。早期 AMD 患者的尸检 RPE 表现出 Bmp6 水平降低。由于氧化应激与 AMD 发病机制相关，并下调培养的 RPE 细胞中的 Bmp6，因此在早期 AMD 的 RPE 细胞中观察到的 Bmp6 水平降低可能导致 AMD 中的铁积累。这反过来又可能引发氧化应激和铁积累的恶性循环，从而加重 AMD 和其他具有遗传性或获得性铁过量的疾病。
