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      Bone morphogenetic protein 6 (BMP-6) modulates lung function, pulmonary iron levels and cigarette smoke-induced inflammation

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          BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism.

          Juvenile hemochromatosis is an iron-overload disorder caused by mutations in the genes encoding the major iron regulatory hormone hepcidin (HAMP) and hemojuvelin (HFE2). We have previously shown that hemojuvelin is a co-receptor for bone morphogenetic proteins (BMPs) and that BMP signals regulate hepcidin expression and iron metabolism. However, the endogenous BMP regulator(s) of hepcidin in vivo is unknown. Here we show that compared with soluble hemojuvelin (HJV.Fc), the homologous DRAGON.Fc is a more potent inhibitor of BMP2 or BMP4 but a less potent inhibitor of BMP6 in vitro. In vivo, HJV.Fc or a neutralizing antibody to BMP6 inhibits hepcidin expression and increases serum iron, whereas DRAGON.Fc has no effect. Notably, Bmp6-null mice have a phenotype resembling hereditary hemochromatosis, with reduced hepcidin expression and tissue iron overload. Finally, we demonstrate a physical interaction between HJV.Fc and BMP6, and we show that BMP6 increases hepcidin expression and reduces serum iron in mice. These data support a key role for BMP6 as a ligand for hemojuvelin and an endogenous regulator of hepcidin expression and iron metabolism in vivo.
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            Novel regulators of bone formation: molecular clones and activities

            Protein extracts derived from bone can initiate the process that begins with cartilage formation and ends in de novo bone formation. The critical components of this extract, termed bone morphogenetic protein (BMP), that direct cartilage and bone formation as well as the constitutive elements supplied by the animal during this process have long remained unclear. Amino acid sequence has been derived from a highly purified preparation of BMP from bovine bone. Now, human complementary DNA clones corresponding to three polypeptides present in this BMP preparation have been isolated, and expression of the recombinant human proteins have been obtained. Each of the three (BMP-1, BMP-2A, and BMP-3) appears to be independently capable of inducing the formation of cartilage in vivo. Two of the encoded proteins (BMP-2A and BMP-3) are new members of the TGF-beta supergene family, while the third, BMP-1, appears to be a novel regulatory molecule.
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              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.
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                Author and article information

                Journal
                Mucosal Immunology
                Mucosal Immunol
                Springer Nature
                1933-0219
                1935-3456
                December 12 2018
                Article
                10.1038/s41385-018-0116-2
                9ecf388e-727c-4f5a-bcc2-cefb7e1b1804
                © 2018

                http://www.springer.com/tdm

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