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Paper of the Month: New insight into hemojuvelin regulation of iron homeostasis

09/27/10  Portland, Ore.

Mahta-Peter-UjwalThis month’s featured paper was published in the August 6, 2010 edition of the Journal of Biological Chemistry, and is entitled “Soluble repulsive guidance molecule c/hemojuvelin is a broad spectrum bone morphogenetic protein (BMP) antagonist and inhibits both BMP2- and BMP6-mediated signaling and gene expression.” The research was conducted by Mahta Nili, Doctoral Student, Ujwal Shinde, PhD, Associate Professor, and Peter Rotwein, MD, Professor and Chair, Department of Biochemistry and Molecular Biology. 

The amount of iron is tightly regulated within the body and detrimental consequences arise from both its deficiency and excess. Control is exerted at the level of iron absorption from the small intestine and released from macrophages by a small liver-derived peptide hormone termed hepcidin that blocks both of these processes. In hereditary hemochromatosis excessive iron accumulates in key organs such as the heart, liver, and pancreas, leading to tissue dysfunction and damage. Hepcidin levels are reduced in hemochromatosis, leading to excessive and inappropriate iron absorption. Juvenile hemochromatosis is a rare rapidly progressive form of hereditary hemochromatosis, and without treatment generally leads to death from heart failure or cardiac arrhythmias before the age of 30. Mutations in the protein hemojuvelin are the most common cause of juvenile hemochromatosis, and recent research has demonstrated a key role for hemojuvelin in regulating hepcidin expression in the liver, primarily through incompletely defined interactions with bone morphogenetic proteins (BMPs), growth factors with multiple effects on growth, development, and tissue repair.

Journal of Biological ChemistryResearch in this paper demonstrates direct actions of hemojuvelin on several classes of BMPs, and shows that soluble naturally occurring forms of hemojuvelin can inhibit binding of BMP2 and BMP6 to their cell-surface receptors, thus antagonizing BMP-mediated signaling pathways and blocking BMP-stimulated gene expression in liver cells.  Besides showing that in different cellular contexts hemojuvelin exerts differential effects on BMP actions, key findings of the paper include the demonstration that soluble hemojuvelin is a novel BMP binding protein, as it interacts with different classes of BMPs, suggesting potential therapeutic uses in other cell and tissue types. Indeed, subsequent studies from another group have identified a potential role for hemojuvelin in modulating BMP actions in bone formation, where the growth factor was initially identified, and where it has been used to enhance bone union after severe fractures. 

“Our findings,” said Dr. Rotwein, “demonstrate the sometimes serendipitous nature of basic biomedical investigation. We discovered hemojuvelin as a novel gene expressed in muscle cells as part of another research project, teamed up with Ujwal Shinde because of his expertise in protein analysis and function, and followed up other observations to study the biochemistry of hemojuvelin’s actions on BMPs. Now we have a reagent that could be used to modify the effects of BMPs under different physiological conditions.”


Pictured (from left): Mahta Nili; Peter Rotwein; Ujwal Shinde


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ABOUT THE PAPER OF THE MONTH

The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. A list of all papers compiled by the OHSU Library and published by OHSU faculty during the prior month is also provided here. The monthly paper summary is selected by Associate Dean for Basic Science Mary Stenzel-Poore, PhD, and reviewed by Dean Mark Richardson, MD, MBA, and Vice President/Senior Associate Dean for Research Dan Dorsa, PhD.