Lack of the bone morphogenetic protein BMP6 induces massive iron overload

Meynard, Delphine; Kautz, Léon; Darnaud, Valérie; Canonne-Hergaux, François; Coppin, Hélène; Roth, Marie-Paule

doi:10.1038/ng.320

Cited by 587Iron Metabolism and DisordersTGF-β signaling in diseasesNeurological diseases and metabolism

Lack of the bone morphogenetic protein BMP6 induces massive iron overload

Meynard, Delphine, Kautz, Léon, Darnaud, Valérie, Canonne-Hergaux, François, Coppin, Hélène, Roth, Marie-Paule·2009·Nature Genetics

DOI 10.1038/ng.320

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Abstract

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 vivo, 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.

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Activation of signaling through HFE, TFR1, TFR2, or HJV increases hepcidin transcription in a SMAD-dependent fashion.
“Activation of signaling through the hemochromatosis protein HFE, TFR1, TFR2, or hemojuvelin (HJV), which acts as a co-receptor for bone morphogenetic protein 6 (BMP6), increases hepcidin transcription in a SMAD-dependent fashion.”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [202]

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Authors: Meynard, D., Kautz, L., Darnaud, V., Canonne-Hergaux, F., Coppin, H., & Roth, M.-P.
Affiliations: Université Toulouse III - Paul Sabatier (FR)
Corresponding author: Roth, Marie-Paule
ORCID: Meynard, Delphine
Kautz, Léon
Coppin, Hélène
Venue: Nature Genetics
Publisher: Springer Science and Business Media LLC
Published: 2009-03-01
Volume: 41
Issue: 4
Pages: 478-481
ISSN: 1061-4036 (ISSN-L)
1546-1718
DOI: 10.1038/ng.320
OpenAlex: W1977767277
Cited by: 587
References: 26
Citations by year: 2026: 8 · 2025: 10 · 2024: 14 · 2023: 21 · 2022: 13 · 2021: 42 · 2020: 28 · 2019: 27 · 2018: 28 · 2017: 39 · 2016: 33 · 2015: 32 · 2014: 41 · 2013: 46 · 2012: 44
FWCI: 44.73
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Genetics (publishedVersion)
PubMed (publishedVersion)
HAL (submittedVersion)
Funders: Fondation pour la Recherche Médicale
Topics: Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
Keywords: BMP6, bone morphogenetic proteins, iron overload, iron homeostasis, hepcidin, Smad1, Smad5, Smad8, BMP signaling, juvenile hemochromatosis, HFE gene
MeSH terms: Animals, Gene Expression Regulation, Humans, Iron, Liver, RNA, Messenger, Spleen, Mice, Knockout, Iron Overload, Mice, Bone Morphogenetic Protein 6

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Lack of the bone morphogenetic protein BMP6 induces massive iron overload

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