Bmp6 -/- mice

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 tubes. Despite their severe iron overload, the livers of Bmp6-deficient mice have low levels of phosphorylated Smad 1, Smad 5 and Smad 8, 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.

Interest / Relevance: - Tool for testing the efficacy of agents 1/ for treating iron overload disorders and 2/ for treating anemia The data suggest that BMP6-like agonists may provide an alternative to venesections for treating genetic iron overload disorders (i.e. genetic hemochromatosis ; 1/300 is affected in populations of Northern european origin). The efficacy of such agonists could easily be tested in Bmp6-/- mice.There are two pathways that regulate hepcidin expression: the iron-sensing pathway that requires Bmp6, and the inflammatory pathway that is independent of Bmp6. Bmp6-/- mice are therefore a good model to test the efficacy of antiinflammatory agents in preventing induction of hepcidin and anemia of chronic diseases.

Keywords: BMP6 , iron , anemia , hemochromatosis , inflammation

Publications:

Meynard D Kautz L Darnaud V Canonne-Hergaux F Coppin H Roth MP. Lack of bone morphogenetic protein BMP6 induces massive iron overload. Nature Genetics 2009 (April)Kautz L Meynard D Monnier A Darnaud V Bouvet R Wang RH Deng C Vaulont S Mosser J Coppin H Roth MP. Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6 Smad7 Id1 and Atoh8 in the mouse liver. Blood 2008 112 : 1503-1509.

Reference:

RT00319