Things that go BMP in the liver: bone morphogenetic protein 6 and the control of body iron homeostasis.
Things that go BMP in the liver: bone morphogenetic protein 6 and the control of body iron homeostasis.
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DOI：
10.1002/hep.23106
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发表时间：
2009-07-01
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影响因子：
--
通讯作者：
Anderson, Gregory J
中科院分区：
文献类型：
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作者：
Anderson, Gregory J
铁调素是肠道铁吸收的关键调节因子，其表达可在体外由多种骨形态发生蛋白 (BMP) 诱导，包括 BMP2、BMP4 和 BMP9（参考文献 1、2）。然而，与 BMP6 不同，其他 BMP 的表达在体内不受铁在 mRNA 水平的调节，并且它们与铁稳态的相关性尚不清楚。我们在此表明，对小鼠中的 Bmp6 进行靶向破坏会导致铁在肝脏、外分泌胰腺的腺泡细胞、心脏和肾曲小管中快速大量积累。尽管铁超载严重，但 Bmp6 缺陷小鼠的肝脏磷酸化 Smad1、Smad5 和 Smad8 水平较低，并且这些 Smad 并未显着易位至细胞核。此外，铁调素合成显着减少。这表明 Bmp6 对于铁稳态至关重要，并且它与 Bmp 亚家族的其他成员在功能上不冗余。值得注意的是，Bmp6 缺陷小鼠保留了诱导铁调素响应炎症的能力。 Bmp6 突变小鼠的铁负荷显着高于经典血色病 (Hfe) 相关基因缺陷的小鼠，这表明 BMP6 突变可能会导致患有严重幼年血色病的人类铁超载，而其遗传基础尚未确定。
Expression of hepcidin, a key regulator of intestinal iron absorption, can be induced in vitro by several bone morphogenetic proteins (BMPs), including BMP2, BMP4 and BMP9 (refs. 1, 2). However, in contrast to BMP6, expression of other BMPs is not regulated at the mRNA level by iron in vivo3, and their relevance to iron homeostasis is unclear. We show here that targeted disruption of Bmp6 in mice causes a rapid and massive accumulation of iron in the liver, the acinar cells of the exocrine pancreas, the heart and the renal convoluted tubules. Despite their severe iron overload, the livers of Bmp6-deficient mice have low levels of phosphorylated Smad1, Smad5 and Smad8, and these Smads are not significantly translocated to the nucleus. In addition, hepcidin synthesis is markedly reduced. This indicates that Bmp6 is critical for iron homeostasis and that it is functionally nonredundant with other members of the Bmp subfamily. Notably, Bmp6-deficient mice retain their capacity to induce hepcidin in response to inflammation. The iron burden in Bmp6 mutant mice is significantly greater than that in mice deficient in the gene associated with classical hemochromatosis (Hfe), suggesting that mutations in BMP6 might cause iron overload in humans with severe juvenile hemochromatosis for which the genetic basis has not yet been characterized.