Lack of the bone morphogenetic protein BMP6 induces massive iron overload.
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.
Meynard
Delphine
D
Inserm, U563, Toulouse, France.
Kautz
Léon
L
Darnaud
Valérie
V
Canonne-Hergaux
François
F
Coppin
Hélène
H
Roth
Marie-Paule
MP
D000818:Animals; D055418:Bone Morphogenetic Protein 6 / Q000172:deficiency* / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D007501:Iron / Q000378:metabolism; D019190:Iron Overload / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D013154:Spleen / Q000378:metabolism
C525816:BMP6 protein, human; C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; D012333:RNA, Messenger; D007501:Iron