Bone morphogenetic protein 2 controls iron homeostasis in mice independent of Bmp6
Open accessAbstract
Hepcidin is a key iron regulatory hormone that controls expression of the iron exporter ferroportin to increase the iron supply when needed to support erythropoiesis and other essential functions, but to prevent the toxicity of iron excess. The bone morphogenetic protein (BMP)-SMAD signaling pathway, through the ligand BMP6 and the co-receptor hemojuvelin, is a central regulator of hepcidin transcription in the liver in response to iron. Here, we show that dietary iron loading has a residual ability to induce Smad signaling and hepcidin expression in Bmp6-/- mice, effects that are blocked by a neutralizing BMP2/4 antibody. Moreover, BMP2/4 antibody inhibits hepcidin expression and induces iron loading in wildtype mice, whereas a BMP4 antibody has no effect. Bmp2 mRNA is predominantly expressed in endothelial cells of the liver, where its baseline expression is higher, but its induction by iron is less robust than Bmp6. Mice with a conditional ablation of Bmp2 in endothelial cells exhibit hepcidin deficiency, serum iron overload, and tissue iron loading in liver, pancreas and heart, with reduced spleen iron. Together, these data demonstrate that in addition to BMP6, endothelial cell BMP2 has a non-redundant role in hepcidin regulation by iron.
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BMP2 is less iron sensitive and is highly expressed in basal conditions.
“BMP2 is less iron sensitive and is highly expressed in basal conditions.44,45”
From Iron metabolism and iron disorders revisited in the hepcidin era (2020) · cites this paper as [45]
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Cites
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Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression
Babitt, J. L., Huang, F. W., Wrighting, D. M., Xia, Y., Sidis, Y., Samad, T. A., Campagna, J. A., Chung, R. T., Schneyer, A. L., Woolf, C. J., et al. (2006) · Nature Genetics · doi:10.1038/ng1777 · Cited by 1,026 · cited 2× · see citing works
“BMP6 is produced in liver endothelial cells in response to iron loading(9,10) and acts in a paracrine fashion on hepatocytes to bind the co-receptor hemojuvelin (HJV, also known as HFE2) and BMP type I and type II receptors to induce phosphorylation of SMAD1/5/8 proteins, which complex with SMAD4 and translocate to th…”
BackgroundMethodMutations in HFE2 cause iron overload in chromosome 1q–linked juvenile hemochromatosis
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Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats
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Self-citationIneffective erythropoiesis and regulation of iron status in iron loading anaemias
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“A clinical scenario including liver cirrhosis, hepatocellular cancer, cardiomyopathy, and diabetes mellitus characterizes diseases that lead to the accumulation of iron in humans, including hereditary hemochromatosis and iron loading anemias.(4,5) For these reasons, iron concentration at the cellular and organismal le…”
BackgroundIn anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2
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Iron metabolism and iron disorders revisited in the hepcidin era
Camaschella, C., Nai, A., & Silvestri, L. (2020) · Haematologica · doi:10.3324/haematol.2019.232124 · Cited by 734 · see citing works
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Self-citationErythroferrone inhibits the induction of hepcidin by BMP6
Arezes, J., Foy, N., McHugh, K., Sawant, A., Quinkert, D., Terraube, V., Brinth, A., Tam, M., LaVallie, E. R., Taylor, S., et al. (2018) · Blood · doi:10.1182/blood-2018-06-857995 · Cited by 277 · see citing works
Iron and innate antimicrobial immunity-depriving the pathogen, defending the host
Nairz, M., Dichtl, S., Schroll, A., Haschka, D., Tymoszuk, P., Theurl, I., & Weiss, G. (2018) · Journal of Trace Elements in Medicine and Biology · doi:10.1016/j.jtemb.2018.03.007 · Cited by 123 · see citing works
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- Authors
- Canali, S., Wang, C., Zumbrennen‐Bullough, K. B., Bayer, A., & Babitt, J. L.
- Affiliations
- Harvard University (US)
- Corresponding author
- Babitt, Jodie L.
- Venue
- American Journal of Hematology
- Publisher
- Wiley
- Published
- 2017-09-25
- Volume
- 92
- Issue
- 11
- Pages
- 1204-1213
- ISSN
- 0361-8609 (ISSN-L)
- 1096-8652
- PMC
- PMC5986189
- OpenAlex
- W2749233178
- Cited by
- 133
- References
- 9
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 11 · 2023: 25 · 2022: 9 · 2021: 19 · 2020: 16 · 2019: 12 · 2018: 16
- FWCI
- 9.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal of Hematology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- JLB (RO1-DK087727)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Micronutrient Interactions and Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- BMP-2, iron homeostasis, hepcidin, BMP6, BMP signaling, hemojuvelin, ferroportin, endothelial cells, iron overload, spleen iron
- MeSH terms
- Animals, Antibodies, Monoclonal, Female, Gene Expression Regulation, Homeostasis, Iron, Kupffer Cells, Liver, Male, Phosphorylation, Mice, Knockout, Iron Overload, Hepatocytes, Endothelial Cells, Mice, Smad1 Protein, Smad5 Protein, Bone Morphogenetic Protein 2, Bone Morphogenetic Protein 4, Bone Morphogenetic Protein 6, Hepcidins
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