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Lack of the bone morphogenetic protein BMP6 induces massive iron overload

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 vivo3, 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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Figure 1: Effect of Bmp6 deficiency on serum transferrin saturation, hepatic and splenic iron concentrations, hepcidin gene expression and hepcidin response to LPS treatment in mice.
Figure 2: Histological examination of iron loading.
Figure 3: Lack of significant phospho-Smad1/5/8 staining in the hepatocyte nuclei of Bmp6-deficient mice.
Figure 4: Increased Dmt1 and ferroportin expression in the proximal duodenum of Bmp6-deficient mice.

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Acknowledgements

The authors thank E. Robertson (Dunn School of Pathology, University of Oxford) for kindly providing the Bmp6-deficient mice, C. Rouanet for excellent technical assistance, J. Seumois and M. Calise (Service de Zootechnie, IFR30, Toulouse) for their help with the mouse breeding, and S. Allart (Cellular Imaging platform, IFR30), F. Capilla and T. Al Saati (Experimental Histopathology platform, IFR30) for skilled advice. This work was supported in part by grants from the Agence Nationale pour la Recherche (ANR, programme IRONGENES), the European Commission (LSHM-CT-2006-037296: EUROIRON1) and the Fondation pour la Recherche Médicale (to L.K.).

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D.M., L.K. and V.D. performed phenotype assessment, analyzed data and reviewed the paper; F.C.-H. provided antibodies and technical advice; H.C. and M.-P.R. conceived the project and wrote the manuscript. The last two senior authors contributed equally to the work.

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Correspondence to Marie-Paule Roth.

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Supplementary Figures 1–7 and Supplementary Table 1 (PDF 1311 kb)

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Meynard, D., Kautz, L., Darnaud, V. et al. Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet 41, 478–481 (2009). https://doi.org/10.1038/ng.320

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