Methods and compositions for regulating iron homeostasis by modulation of BMP-6
Modulation of iron homeostasis by regulating BMP-6 activity is provided. Methods of using BMP-6 and BMP-6 protein-specific reagents, such as antibodies, for altering serum iron levels in humans are provided. Such antibodies are useful in pharmaceutical compositions for the prevention and treatment of hemochromatosis and anemia of inflammation.
1. A method for increasing serum iron levels in a subject, said method comprising administering to said subject an effective amount of a pharmaceutical composition sufficient for modulating BMP-6 signaling at a level sufficient to increase serum iron levels in the subject, wherein the pharmaceutical composition is a monoclonal antibody that specifically binds mature BMP-6 protein or fragments thereof, and wherein the antibody competitively inhibits BMP-6 binding to soluble human hemojuvelin protein.
2. The method of claim 1 , wherein administering the composition reduces BMP-6 signaling.
3. The method of claim 1 , wherein the mature BMP-6 comprises the amino acid sequence of SEQ ID NO:2.
4. The method of claim 1 , wherein the composition binds BMP-6 within residues TQSQDVARVSSASDY (SEQ ID NO:3).
5. The method of claim 1 , wherein the soluble human hemojuvelin protein is HJV.Fc or HJV.His.
6. The method of claim 1 , wherein administering the composition reduces hemojuvelin-mediated induction of hepcidin expression.
7. The method of claim 6 , wherein the composition is administered in an amount sufficient to inhibit an interaction between hemojuvelin and BMP-6.
8. The method of claim 7 , wherein the composition preferably inhibits human BMP-6 over BMP-2, BMP-4, BMP-5, BMP-7 or BMP-9.
9. The method of claim 8 , wherein the composition binds BMP-6 with at least 5-fold greater affinity that BMP-7.
10. The method of claim 1 , wherein the administration of the composition results in increased serum transferrin saturation in the subject.
11. A method of treating a disorder of serum iron deficiency in a subject in need thereof comprising administering to said subject the antibody of claim 1 .
12. The method of claim 11 , wherein the disorder of serum iron deficiency is anemia.