After an erythropoietic stimulation such as hemorrhage, the levels of hormone erythropoietin (EPO) increase in circulation. EPO stimulates erythroblasts, the precursors of red blood cells in the bone marrow, to secrete the hormone erythroferrone (ERFE). ERFE suppresses hepcidin production in the liver, which in turn results in greater iron availability for new red-blood-cell synthesis.
Erythroferrone is greatly increased when red-blood-cell production is stimulated, such as aft er bleeding or in response to anemia. The erythroferrone hormone acts by regulating the main iron hormone, hepcidin, which controls the absorption of iron from food and the distribution of iron in the body. Increased erythroferrone suppresses hepcidin and allows more iron to be made available for red-blood-cell production.
“If there is too-little iron, it causes anemia. If there is too-much iron, the iron overload accumulates in the liver and organs, where it is toxic and causes damage,” says Tomas Ganz, MD ’78 (RES ’81, FEL ’83), PhD, professor of medicine and pathology. “Modulating the activity of erythroferrone could be a viable strategy for the treatment of iron disorders of both overabundance and scarcity.”
Researchers fi rst focused on what happens in the bone marrow aft er hemorrhage. From there, they focused on a specifi c protein that was secreted into the blood. This protein attracted their attention because it belonged to a family of proteins involved in cell-to-cell communication. Using recombinant-DNA technology, they showed that the hormone suppressed the production of hepcidin and demonstrated the effect it had on iron metabolism.
The team foresees that the discovery could help people with a common congenital blood disorder called Cooley’s anemia, also known as thalassemia, which causes excessive destruction of red blood cells and of their progenitors in the bone marrow. Many of these patients require regular blood transfusions throughout their lives. Most iron overload is attributed to the iron content of transfused blood; however, even patients who are rarely, or never, transfused can also develop iron overload.
“Overproduction of erythroferrone may be a major cause of iron overload in untransfused patients and may contribute to iron overload in transfused patients,” says Elizabeta Nemeth, PhD, co-director of the UCLA Center for Iron Disorders. “The identification of erythroferrone can potentially allow researchers and drug developers to target the hormone for a specific treatment to prevent iron overload in Cooley’s anemia.”
The discovery could also lead to treatments for other common anemia-related conditions associated with chronic kidney disease, rheumatologic disorders and other inflammatory diseases. In these conditions, iron is “locked up” by the effect of the hormone hepcidin, whose levels are increased by infl ammation. Erythroferrone, or drugs acting like it, could suppress hepcidin and make more iron available for red-blood-cell production. The next stage of research is to understand the role of the new hormone in various blood diseases and study the molecular mechanisms through which erythroferrone regulates hepcidin. A Game-changer in the Fight against Melanoma
ldquo;Identification of erythroferrone as an erythroid regulator of iron metabolism,” Nature Genetics, July 2014