Division of Nephrology, Program in Membrane Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Hepatology. 2020 Aug;72(2):642-655. doi: 10.1002/hep.31048. Epub 2020 May 22.
Bone morphogenetic proteins BMP2 and BMP6 play key roles in systemic iron homeostasis by regulating production of the iron hormone hepcidin. The homeostatic iron regulator (HFE) also regulates hepcidin through a mechanism that intersects with the BMP-mothers against decapentaplegic homolog 1/5/8 (SMAD1/5/8) pathway. However, the relative roles of BMP2 compared with BMP6 and whether HFE regulates hepcidin through a BMP2-dependent mechanism remain uncertain.
We therefore examined the iron phenotype of mice deficient for both Bmp2 and Bmp6 or both Bmp2 and Hfe compared with single knockout (KO) mice and littermate controls. Eight-week-old double endothelial Bmp6/Bmp2 KO mice exhibited a similar degree of hepcidin deficiency, serum iron overload, and tissue iron overload compared with single KO mice. Notably, dietary iron loading still induced liver SMAD5 phosphorylation and hepcidin in double Bmp6/endothelial Bmp2 KO mice, although no other BMP ligand mRNAs were increased in the livers of double KO mice, and only Bmp6 and Bmp2 mRNA were induced by dietary iron loading in wild-type mice. In contrast, double Hfe/endothelial Bmp2 KO mice exhibited reduced hepcidin and increased extrahepatic iron loading compared to single Hfe or endothelial Bmp2 KO mice. Liver phosphorylated SMAD5 and the SMAD1/5/8 target inhibitor of DNA binding 1 (Id1) mRNA were also reduced in double Hfe/endothelial Bmp2 KO compared with single endothelial Bmp2 KO female mice. Finally, hepcidin and Id1 mRNA induction by homodimeric BMP2, homodimeric BMP6, and heterodimeric BMP2/6 were blunted in Hfe KO primary hepatocytes.
These data suggest that BMP2 and BMP6 work collaboratively to regulate hepcidin expression, that BMP2-independent and BMP6-independent SMAD1/5/8 signaling contributes a nonredundant role to hepcidin regulation by iron, and that HFE regulates hepcidin at least in part through a BMP2-independent but SMAD1/5/8-dependent mechanism.
骨形态发生蛋白 2（BMP2）和 BMP6 通过调节铁激素铁调素的产生，在维持全身铁稳态方面发挥着关键作用。铁稳态调节因子（HFE）还通过一种与 BMP-抗凋亡蛋白 1/5/8（SMAD1/5/8）途径相交的机制来调节铁调素。然而，BMP2 与 BMP6 相比的相对作用，以及 HFE 是否通过 BMP2 依赖性机制来调节铁调素，仍不确定。
因此，我们比较了双内皮 Bmp2 和 Bmp6 缺陷或双 Bmp2 和 Hfe 缺陷与单基因敲除（KO）小鼠和同窝对照小鼠的铁表型。8 周龄的双内皮 Bmp6/Bmp2 KO 小鼠与单 KO 小鼠相比，表现出相似程度的铁调素缺乏、血清铁过载和组织铁过载。值得注意的是，尽管双 KO 小鼠肝脏中没有其他 BMP 配体 mRNA 增加，并且只有 Bmp6 和 Bmp2 mRNA 被膳食铁负荷诱导，膳食铁负荷仍诱导双 Bmp6/内皮 Bmp2 KO 小鼠肝脏中 SMAD5 磷酸化和铁调素。相反，与单 Hfe 或内皮 Bmp2 KO 小鼠相比，双 Hfe/内皮 Bmp2 KO 小鼠的铁调素减少，肝外铁负荷增加。与单内皮 Bmp2 KO 雌性小鼠相比，双 Hfe/内皮 Bmp2 KO 小鼠的肝磷酸化 SMAD5 和 SMAD1/5/8 靶标抑制物 1（Id1）mRNA 也减少。最后，Hfe KO 原代肝细胞中同源二聚体 BMP2、同源二聚体 BMP6 和异源二聚体 BMP2/6 诱导的铁调素和 Id1 mRNA 的诱导作用减弱。
这些数据表明，BMP2 和 BMP6 协同工作来调节铁调素的表达，BMP2 非依赖性和 BMP6 非依赖性 SMAD1/5/8 信号通路对铁调节铁调素起着非冗余作用，HFE 至少部分通过 BMP2 非依赖性但 SMAD1/5/8 依赖性机制来调节铁调素。
