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Blood, 15 October 2005, Vol. 106, No. 8, pp. 2884-2889. Prepublished online as a Blood First Edition Paper on July 5, 2005; DOI 10.1182/blood-2005-05-1845. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: 2005-05-1845v1 106/8/2884    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lin, L. Articles by Ganz, T. Search for Related Content PubMed PubMed Citation Articles by Lin, L. Articles by Ganz, T. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 6, 2005 Accepted June 20, 2005 Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin Lan Lin, Y. Paul Goldberg, and Tomas Ganz* Departments of Medicine and Pathology, David Geffen School of Medicine, Los Angeles, CA, USA Xenon Pharmaceuticals Inc., Burnaby, BC, Canada * Corresponding author; email: tganz{at}mednet.ucla.edu. Mutations in a recently identified gene HJV (also called HFE2, or repulsive guidance molecule C, RgmC) are the major cause of juvenile hemochromatosis (JH). The protein product of HJV, hemojuvelin, contains a C-terminal GPI-anchor, suggesting that it can be present in either a soluble or a cell-associated form. Patients with HJV hemochromatosis have low urinary levels of hepcidin, the principal iron-regulatory hormone secreted by the liver. However, neither the specific role of hemojuvelin in maintaining iron homeostasis, nor its relationship to hepcidin has been experimentally established. In this study we used hemojuvelin-specific siRNAs to vary hemojuvelin mRNA concentration, and showed that cellular hemojuvelin positively regulated hepcidin mRNA expression, independently of the IL-6 pathway. We also showed that recombinant soluble hemojuvelin (rs-hemojuvelin) suppressed hepcidin mRNA expression in primary human hepatocytes in a log-linear dose-dependent manner, suggesting binding competition between soluble and cell-associated hemojuvelin. Soluble hemojuvelin was found in human sera at concentrations similar to those required to suppress hepcidin mRNA in vitro. In cells engineered to express hemojuvelin, soluble hemojuvelin release was progressively inhibited by increasing iron concentrations. We propose that soluble and cell-associated hemojuvelin reciprocally regulate hepcidin expression in response to changes in extracellular iron concentration. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A.-S. Zhang, F. Yang, J. Wang, H. Tsukamoto, and C. A. Enns Hemojuvelin-Neogenin Interaction Is Required for Bone Morphogenic Protein-4-induced Hepcidin Expression J. Biol. Chem., August 21, 2009; 284(34): 22580 - 22589. [Abstract] [Full Text] [PDF] A. J. Ramsay, J. D. Hooper, A. R. Folgueras, G. Velasco, and C. Lopez-Otin Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis Haematologica, June 1, 2009; 94(6): 840 - 849. [Abstract] [Full Text] [PDF] G. Ramey, J.-C. Deschemin, and S. 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