Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism.
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.
Yu
Paul B
PB
Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA.
Hong
Charles C
CC
Sachidanandan
Chetana
C
Babitt
Jodie L
JL
Deng
Donna Y
DY
Hoyng
Stefan A
SA
Lin
Herbert Y
HY
Bloch
Kenneth D
KD
Peterson
Randall T
RT
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000037:antagonists & inhibitors; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D064451:Hepcidins; D007501:Iron / Q000097:blood / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism
D023181:Antimicrobial Cationic Peptides; D019485:Bone Morphogenetic Proteins; C579599:Hamp protein, mouse; D064451:Hepcidins; D011720:Pyrazoles; D011743:Pyrimidines; D051785:Smad Proteins; D054852:Small Molecule Libraries; C516138:dorsomorphin; D007501:Iron; D052005:Bone Morphogenetic Protein Receptors, Type I