Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism
Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism
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DOI：
10.1038/nchembio.2007.54
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发表时间：
2008-01-01
影响因子：
14.8
通讯作者：
Peterson, Randall T.
中科院分区：
文献类型：
--
作者：
Yui, Paul B.;Hong, Charles C.;Peterson, Randall T.
骨形态发生蛋白（BMP）信号协调发育模式，并在成熟生物体中具有重要的生理作用。在这里，我们描述了第一个已知的小分子抑制剂的BMP信号dorsomorphin，我们确定在屏幕上的化合物，干扰背腹轴形成斑马鱼。我们发现dorsomorphin选择性地抑制BMP I型受体ALK 2、ALK 3和ALK 6，从而阻断BMP介导的SMAD 1/5/8磷酸化、靶基因转录和成骨分化。使用dorsomorphin，我们研究了BMP信号在铁稳态中的作用。在体外，dorsomorphin抑制全身性铁调节剂hepcidin的BMP-、hemojuvelin-和白细胞介素6-刺激的表达，这表明BMP受体通过所有这些刺激调节hepcidin诱导。在体内，铁的全身性攻击迅速诱导SMAD 1/5/8磷酸化和hepcidin在肝脏中的表达，而用dorsomorphin治疗阻断SMAD 1/5/8磷酸化，使hepcidin表达正常化并增加血清铁水平。这些研究结果表明，铁铁调素稳态的肝脏BMP信号转导的重要生理作用。
Bone morphogenetic protein (BMP) signals coordinate developmental patterning and have essential physiological roles in mature organisms. Here we describe the first known small-molecule inhibitor of BMP signaling-dorsomorphin, which we identified in a screen for compounds that perturb dorsoventral axis formation in zebrafish. We found that dorsomorphin selectively inhibits the BMP type I receptors ALK2, ALK3 and ALK6 and thus blocks BMP-mediated SMAD1/5/8 phosphorylation, target gene transcription and osteogenic differentiation. Using dorsomorphin, we examined the role of BMP signaling in iron homeostasis. in vitro, dorsomorphin inhibited BMP-, hemojuvelin- and interleukin 6-stimulated expression of the systemic iron regulator hepcidin, which suggests that BMP receptors regulate hepcidin induction by all of these stimuli. In vivo, systemic challenge with iron rapidly induced SMADI/5/8 phosphorylation and hepcidin expression in the liver, whereas treatment with dorsomorphin blocked SMAD1/5/8 phosphorylation, normalized hepcidin expression and increased serum iron levels. These findings suggest an essential physiological role for hepatic BMP signaling in iron-hepcidin homeostasis.