Iron-Induced Expression of Bone Morphogenic Protein 6 in Intestinal Cells Is the Main Regulator of Hepatic Hepcidin Expression In Vivo

Abstract

Recent studies identified bone morphogenic protein 6 (BMP6) as a key regulator of hepatic hepcidin expression and iron metabolism, but the cellular source of BMP6 and the reason for its specific effect on hepatocytes are unknown. BMP and hepcidin expression upon iron sensing were analyzed in vivo in BMP6(-/-) and BMP6(+/+) mice and ex vivo in tissue and in vitro in cells of the liver and the small intestine. BMP6(-/-) mice developed severe hepatic iron accumulation and reduced hepcidin expression with increasing age. This phenotype could be triggered in younger BMP6(-/-) mice by dietary or parenteral iron application. Furthermore, both treatments induced a marked up-regulation of BMP6 expression in the small intestine of BMP6(+/+) mice. Ex vivo treatment of intestinal tissue of BMP6(+/+) mice with iron sulfate or holo-transferrin confirmed epithelial cells as an inducible source of BMP6. In contrast, iron overload did not promote a striking induction of BMP6 expression in hepatocytes or macrophages. Furthermore, iron-supplemented diet induced a compensatory up-regulation of BMP2, BMP4, and BMP9 in the small intestine of BMP6(-/-) mice that was apparently not sufficient to assure iron homeostasis. As a potential explanation, analysis of hepatocytes revealed an expression pattern of BMP receptor subunits preferentially used by BMP6, and treatment of hepatocytes with different recombinant BMPs identified BMP6 as the most potent stimulator of hepcidin expression. Epithelial cells of the small intestine are the predominant cellular source of BMP6 upon iron sensing. Our findings reveal a previously unknown mechanism in which the small intestine controls iron homeostasis.