Use of modulators of compounds of TGF-β superfamily to regulate hepcidin-mediated iron metabolism
The present invention provides new systems and strategies for the regulation of iron metabolism in mammals. In particular methods of using agonists and antagonists of TGF-β superfamily members to modulate the expression or activity of hepcidin, a key regulator of iron metabolism, are described. The inventive methods find applications in the treatment of diseases associated with iron overload, such as juvenile hemochromatosis and adult hemochromatosis, and in the treatment of diseases associated with iron deficiency, such as anemia of chronic disease and EPO resistant anemia in end-stage of renal disease. The present invention also relates to screening tools and methods for the development of novel drugs and therapies for treating iron metabolism disorders.
1. A method of increasing iron levels in a subject in need thereof, said method comprising administering to said subject a fusion protein comprising:
(a) an extracellular domain or soluble portion of human hemojuvelin (HJV), wherein HJV comprises the amino acid sequence of SEQ ID NO:24, and wherein said domain or portion comprises an alanine, an aspartic acid or a deletion at position 172 of SEQ ID NO:24; and
(b) Fc;
wherein said composition is administered in an amount effective to increase iron levels in said subject.
2. The method of claim 1 , wherein said Fc is human Fc.
3. The method of claim 1 , wherein the fusion protein is administered with a pharmaceutically acceptable carrier.
4. The method of claim 1 , wherein said extracellular domain or soluble portion of HJV lacks an N-terminal signal sequence.
5. The method of claim 1 , wherein the extracellular domain or soluble portion of HJV comprises amino acids 1-400 of SEQ ID NO:24.
6. The method of claim 1 , wherein said subject suffers from an iron deficiency.
7. The method of claim 6 , wherein said iron deficiency is caused by pregnancy, menstruation, or blood loss due to injury.
8. The method of claim 6 , wherein the extracellular domain or soluble portion of HJV comprises amino acids 35-400 of SEQ ID NO:24.
9. The method of claim 6 , wherein said iron deficiency is selected from the group consisting of anemia of chronic disease, iron deficiency, anemia, functional iron deficiency, and microcytic anemia.
10. The method of claim 9 , wherein said anemia of chronic disease is associated with chronic bacterial endocarditis, osteomyelitis, rheumatic fever, ulcerative colitis, a neoplastic disorder, infection, or inflammation.
11. The method of claim 10 , wherein said infection is a pulmonary abscess, or tuberculosis.
12. The method of claim 10 , wherein said inflammation is caused by rheumatoid arthritis, systemic lupus erythrematosus, Chrohn's disease, hepatitis, or inflammatory bowel disease.