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Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism

Abstract

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 SMAD1/5/8 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.

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Figure 1: Dorsomorphin induces dorsalization in zebrafish embryos.
Figure 2: Dorsomorphin inhibits BMP-mediated activation of SMAD by inhibiting BMP type I receptor function.
Figure 3: Dorsomorphin inhibits osteogenic differentiation in vitro and bone mineralization in vivo.
Figure 4: Dorsomorphin inhibits BMP- and HJV-induced hepcidin expression in cultured hepatoma-derived cells.
Figure 5: Dorsomorphin inhibits iron-mediated BMP-responsive SMAD activation and expression of hepcidin.

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Acknowledgements

We are grateful to H. Beppu, C. MacRae and I. Drummond for feedback and advice and to A. Graveline for technical assistance. We thank P. ten Dijke (Leiden University Medical Center) for the BRE-Luc and the CAGA-Luc, and we thank K. Miyazono (University of Tokyo) for the caALK2, caALK3, caALK4, caALK5, caALK6 and caALK7. This work was supported by US National Institutes of Health grants HL079943 (P.B.Y.), HL081535 (C.C.H.), DK075846 (J.L.B.), DK071837 (H.Y.L.), HL074352 (K.D.B.), HL079267 (R.T.P.) and CA118498 (R.T.P.). This work was also supported by a Pulmonary Hypertension Association Mentored Clinical Scientist Award (P.B.Y.) and a grant from the GlaxoSmithKline Research & Education Foundation for Cardiovascular Disease (P.B.Y.).

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P.B.Y., C.C.H., C.S., J.L.B., H.Y.L., K.D.B and R.T.P. designed experiments, performed experiments, analyzed data and helped write the manuscript. D.Y.D. and S.A.H. performed experiments. K.D.B. and R.T.P. contributed equally as senior authors to this work.

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Correspondence to Kenneth D Bloch or Randall T Peterson.

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Yu, P., Hong, C., Sachidanandan, C. et al. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol 4, 33–41 (2008). https://doi.org/10.1038/nchembio.2007.54

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