Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance
Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance
复制标题
DOI：
10.1172/jci31342
复制
发表时间：
2007-07-01
影响因子：
15.9
通讯作者：
Lin, Herbert Y.
中科院分区：
文献类型：
--
作者：
Babitt, Jodie L.;Huang, Franklin W.;Lin, Herbert Y.
全身铁平衡受肝脏分泌的多肽荷尔蒙--海普西丁的调节。通过减少细胞表面铁出口蛋白的表达，海普西丁减少了肠道中铁的吸收和网状内皮库中铁的释放。海普西丁过量参与了慢性疾病贫血的发病机制，而海普西丁缺乏在铁负荷紊乱血色病的发病机制中起着关键作用。我们最近发现，血凝素是骨形态发生蛋白(BMP)信号的辅助受体，而BMP信号在体外正向调节肝细胞中的海普西丁的表达。在体内，我们发现BMP-2的应用增加了海普西丁的表达，降低了血清铁的水平。我们还发现，在体外，可溶性血凝素(HJV.Fc)选择性地抑制BMP诱导的海普西丁的表达，而在体内，给予HJV.Fc可降低海普西丁的表达，增加铁门蛋白的表达，动员脾的铁储备，并增加血清铁水平。这些数据支持BMP信号通路的调节者在治疗铁超载和慢性病贫血中的作用。
Systemic iron balance is regulated by, hepcidin, a peptide hormone secreted by the liver. By decreasing cell surface expression of the iron exporter ferroportin, hepcidin decreases iron absorption from the intestine and iron release from reticuloendothelial stores. Hepcidin excess has been implicated in the pathogenesis of anemia of chronic disease, while hepcidin deficiency has a key role in the pathogenesis of the iron overload disorder hemochromatosis. We have recently shown that hemojuvelin is a coreceptor for bone morphogenetic protein (BMP) signaling and that BMP signaling positively regulates hepcidin expression in liver cells in vitro. Here we show that BMP-2 administration increases hepcidin expression and decreases serum iron levels in vivo. We also show that soluble hemojuvelin (HJV.Fc) selectively inhibits BMP induction of hepcidin expression in vitro and that administration of HJV.Fc decreases hepcidin expression, increases ferroportin expression, mobilizes splenic iron stores, and increases serum iron levels in vivo. These data support a role for modulators of the BMP signaling pathway in treating diseases of iron overload and anemia of chronic disease.