Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice.

Abstract

Bone morphogenetic protein (BMP) signaling induces hepatic expression of the peptide hormone hepcidin. Hepcidin reduces serum iron levels by promoting degradation of the iron exporter ferroportin. A relative deficiency of hepcidin underlies the pathophysiology of many of the genetically distinct iron overload disorders, collectively termed hereditary hemochromatosis. Conversely, chronic inflammatory conditions and neoplastic diseases can induce high hepcidin levels, leading to impaired mobilization of iron stores and the anemia of chronic disease. Two BMP type I receptors, Alk2 (Acvr1) and Alk3 (Bmpr1a), are expressed in murine hepatocytes. We report that liver-specific deletion of either Alk2 or Alk3 causes iron overload in mice. The iron overload phenotype was more marked in Alk3- than in Alk2-deficient mice, and Alk3 deficiency was associated with a nearly complete ablation of basal BMP signaling and hepcidin expression. Both Alk2 and Alk3 were required for induction of hepcidin gene expression by BMP2 in cultured hepatocytes or by iron challenge in vivo. These observations demonstrate that one type I BMP receptor, Alk3, is critically responsible for basal hepcidin expression, whereas 2 type I BMP receptors, Alk2 and Alk3, are required for regulation of hepcidin gene expression in response to iron and BMP signaling.

• Authors: Andrea U Steinbicker, Thomas B Bartnikas, Lisa K Lohmeyer, Patricio Leyton, Claire Mayeur, Sonya M Kao, Alexandra E Pappas, Randall T Peterson, Donald B Bloch, Paul B Yu, Mark D Fleming, Kenneth D Bloch
• Journal: Blood (Blood) Vol. 118 Issue 15 Pg. 4224-30 (Oct 13 2011) ISSN: 1528-0020 [Electronic] United States
• PMID: 21841161 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antimicrobial Cationic Peptides
• Hamp protein, mouse
• Hepcidins
• Activin Receptors, Type I
• Acvr1 protein, mouse
• Bmpr1a protein, mouse
• Bone Morphogenetic Protein Receptors, Type I

Topics

• Activin Receptors, Type I (genetics, metabolism)
• Animals
• Antimicrobial Cationic Peptides (biosynthesis, genetics)
• Bone Morphogenetic Protein Receptors, Type I (genetics, metabolism)
• Cells, Cultured
• Gene Deletion
• Gene Expression Regulation
• Hepatocytes (metabolism)
• Hepcidins
• Iron Overload (genetics, metabolism)
• Mice
• Mice, Mutant Strains
• Signal Transduction (genetics)