BMP Signaling and Iron Homeostasis

Abstract

Iron is an essential nutrient that is critical for fundamental cellular and organismal processes including oxygen transport and energy generation. However, excess iron can catalyze the formation of toxic free oxygen radicals. Cellular and systemic iron homeostasis are therefore tightly regulated to titrate the iron supply to match iron needs. The master regulator of systemic iron homeostasis is the liver hormone hepcidin, which binds and degrades the iron exporter ferroportin to limit iron release from dietary sources and body stores. To maintain normal systemic iron homeostasis, liver hepcidin production is coordinated by a number of signals that communicate body iron needs. Iron deficiency and anemia suppress hepcidin production to increase iron availability for red blood cell production and other essential functions. Conversely, increases in serum or tissue iron stimulate hepcidin production to prevent iron overload. Inflammation also stimulates hepcidin production to restrict iron availability to infectious microorganisms. Abnormal regulation of the hepcidin‐ferroportin axis has a pathogenic role in most disorders of systemic iron homeostasis including the anemia of inflammation, the iron overload disorder hereditary hemochromatosis, and iron‐loading anemias such as beta‐thalassemia. We have discovered a key role for the bone morphogenetic protein (BMP)‐SMAD signaling pathway in controlling liver hepcidin transcription. This talk will present recent insights into how BMP‐SMAD signaling coordinates liver hepcidin transcription in response to body iron levels and the iron demand of red blood cell production to maintain systemic iron homeostasis.