Competitive Regulation of Hepcidin mRNA by Soluble and Cell-Associated Hemojuvelin

Abstract

Disclosed herein are hemojuvelin-specific siRNAs that vary hemojuvelin mRNA concentration. Also disclosed herein, GPI-hemojuvelin positively regulated hepcidin mRNA expression, independently of the IL-6 pathway, whereas soluble hemojuvelin (s-hemojuvelin) suppressed hepcidin mRNA expression in primary human hepatocytes in a log-linear dosedependent manner. Disclosed are compositions and methods for modulating diseases of iron metabolism and hepcidin expression or hepcidin levels.

1 - 14 . (canceled) 
     
     
         15 . The purified polypeptide of  claim 21 , consisting of SEQ ID NO:1. 
     
     
         16 . A pharmaceutical composition comprising the purified polypeptide of  claim 21  and a pharmaceutically acceptable carrier. 
     
     
         17 . A method for monitoring or diagnosing a disease of iron metabolism in a subject comprising assaying the amount of a membrane-associated GPI-linked hemojuvelin, the amount of a soluble hemojuvelin protein, or both in the subject and determining whether the amount is normal or abnormal. 
     
     
         18 . The method of  claim 17 , wherein determining whether the amount is normal or abnormal comprises determining a difference in the amount obtained from the subject relative to the amount in an individual not so afflicted or at such risk; wherein said difference indicates the amount is abnormal. 
     
     
         19 . An expression vector capable of expressing the soluble mammalian hemojuvelin protein of  claim 21 . 
     
     
         20 . A recombinant host comprising the expression vector of  claim 19 . 
     
     
         21 . A purified soluble mammalian hemojuvelin protein. 
     
     
         22 . The purified soluble mammalian hemojuvelin protein of  claim 21 , which lacks its glycophosphatidylinositol anchor. 
     
     
         23 . The purified soluble mammalian hemojuvelin protein of  claim 21 , having a sequence which comprises at least 335 consecutive amino acid residues of SEQ ID NO:1 and suppresses hepcidin mRNA production. 
     
     
         24 . The purified soluble mammalian hemojuvelin protein of  claim 21 , which comprises SEQ ID NO:1.