Possible new drug target for iron deficiency, overload

Possible new drug target for iron deficiency, overload

US researchers have discovered a protein that appears to play an important role in regulating blood levels of iron and suggest it could be a new target for drugs to treat iron deficiency, which is quite common, as well as the much rarer opposite condition, iron overload.

Corresponding author Dr. Wen-Cheng Xiong, a developmental neurobiologist at the Augusta-based Medical College of Georgia Schools of Medicine and Graduate Studies, and colleagues, have written about their discovery in a paper published in this month's issue of the journal Blood.

Iron is an essential nutrient that enters the body in foods like meat, beans, watercress and spinach. All cells use iron but its most important role is to help red blood cells ferry oxygen all over the body.

Anemia is where people don't have enough iron, this is quite common, but much rarer is having toxic levels of iron in the body as results from genetic conditions like juvenile hemochromatosis, and even some blood transfusions.

Xiong and colleagues found that the protein neogenin, already known as a receptor that aids neural development, also appears to play a key role in the way our bodies regulate iron.

Neogenin is a transmembrane protein that is crucial for guiding axons and migrating neurons: it acts as a receptor for netrins, the proteins that do the guiding and also works with molecules called repulsive guidance molecules (RGMs), already known to help regulate iron levels, which led the researchers to suspect perhaps neogenin did something similar.

The neogenin receptor sits on the cell surface and should be an easy target for new drugs to help increase or decrease iron levels, Dr Xiong told the press.

The liver influences blood levels of iron when it secretes a hormone called hepcidin: this controls how much iron circulates in the blood, how much is held in reserve in the spleen, and tells the gut how much to absorb or eliminate, thus maintaining a steady level by tweaking signals for supply, demand and elimination.

But hepcidin itself is influenced by a protein called BMP (bone morphogenetic protein), which is influenced by an RGM gene called hemojuvelin (HJV).

In this study the researchers showed that in mice, neogenin suppressed the release of HJV, and in cell culture, increased expression of HJV led to increased hepcidin expression, while suppression of HJV decreased it.

They wrote that taken altogether, their results suggest that:

"Neogenin regulates iron homeostasis via inhibiting secretion of HJV, an inhibitor of BMP signaling, to enhance BMP signaling and hepcidin expression".

"These results reveal a novel mechanism underlying neogenin regulation of HJV-BMP signaling," they added.

So, in essence, Xiong and colleagues appear to have found that neogenin, which until now was thought only to be involved in neural development, plays a role in keeping iron levels in the blood within certain limits (iron homeostasis), and because it sits on the surface of cells it might be a useful target for new treatments for iron imbalance.

The researchers said their next step was to find out if neogenin expression is up or down in patients with iron deficiency and iron overload, eg anemia and juvenile hemochromatosis.

Xiong predicts neogenin expression will be up in patients with anemia and down in iron-overload conditions.

"If that is verified, drugs to stimulate or inhibit neogenin would be useful," she added.

"Neogenin inhibits HJV secretion and regulates BMP induced hepcidin expression and iron homeostasis."

D-H. Lee, L-J Zhou, Z. Zhou, J-X. Xie, J-U. Jung, Y. Liu, C-X. Xi, L. Mei, and W-C. Xiong

Blood, Jan 2010, Prepublished online January 11, 2010.


Sources: Medical College of Georgia, R&D Systems Inc.

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