Coordination of iron homeostasis by bone morphogenetic proteins: Current understanding and unanswered questions

Abstract

Iron homeostasis is tightly regulated to balance the iron requirement for erythropoiesis and other vital cellular functions, while preventing cellular injury from iron excess. The liver hormone hepcidin is the master regulator of systemic iron balance by controlling the degradation and function of the sole known mammalian iron exporter ferroportin. Liver hepcidin expression is coordinately regulated by several signals that indicate the need for more or less iron, including plasma and tissue iron levels, inflammation, and erythropoietic drive. Most of these signals regulate hepcidin expression by modulating the activity of the bone morphogenetic protein (BMP)-SMAD pathway, which controls hepcidin transcription. Genetic disorders of iron overload and iron deficiency have identified several hepatocyte membrane proteins that play a critical role in mediating the BMP-SMAD and hepcidin regulatory response to iron. However, the precise molecular mechanisms by which serum and tissue iron levels are sensed to regulate BMP ligand production and promote the physical and/or functional interaction of these proteins to modulate SMAD signaling and hepcidin expression remain uncertain. This critical commentary will focus on the current understanding and key unanswered questions regarding how the liver senses iron levels to regulate BMP-SMAD signaling and thereby hepcidin expression to control systemic iron homeostasis.

Keywords: BMP; anemia; hemochromatosis; hepcidin; iron sensing; liver.

Figure 1.. Systemic iron economy and hepcidin-ferroportin axis.

(A) The majority of body iron (3-4 g in adult humans) is contained in red blood cell hemoglobin or stored in ferritin in the liver hepatocytes and macrophages. Blood plasma contains only 2-4 mg of iron where it is normally bound to the protein transferrin (TF). Circulating iron is distributed to consuming tissues for utilization or storage. The major sources of iron export into plasma include release of recycled iron from macrophages that phagocytose old red blood cells, mobilization of stored iron from the liver, and absorption of dietary iron by enterocytes. Red blood cells and the kidney can also export iron into plasma. Minimal iron is lost daily through desquamation or minor blood loss. (B) Hepcidin is the master regulator of systemic iron homeostasis. Produced and secreted by liver hepatocytes, hepcidin acts by posttranslational regulation of its receptor and only known iron exporter ferroportin (FPN), which is expressed in all tissues that export iron into plasma. Hepcidin binds to FPN, blocks iron export, and triggers FPN degradation, resulting in iron sequestration in target cells and lower plasma iron levels. The major signals that regulate hepcidin are iron, erythropoietic drive, and inflammation. Iron deficiency and erythropoiesis suppress hepcidin, promoting iron export into plasma for red blood cell production. Hepcidin is induced by iron to prevent iron overload and is pathologically increased by inflammation to limit iron availability to pathogens.

Figure 2.. Current model of iron sensing and signaling in the liver.

Hepcidin production is regulated transcriptionally by iron, a process dependent on sensing of plasma and tissue iron levels. (A) In high iron conditions, plasma iron concentrations exceed the iron-binding capacity of transferrin (TF) and non-transferrin bound iron (NTBI) appears. Iron is taken up by endothelial cells through unknown mechanisms and stimulates BMP6 and to a lesser extent BMP2 expression. BMP6 transcription is partly controlled by nuclear factor erythroid 2-like 2 (NRF2) in response to iron-induced mitochondrial prooxidants. BMP2 and BMP6 bind hemojuvelin (HJV) and BMP type I and II receptors (ALK2, ALK3, ACVRIIA, BMPR-II; represented by BMPRI/II) on the hepatocyte membrane, forming a complex with neogenin (NEO1). The complex phosphorylates cytoplasmic SMAD1,5,8, which binds SMAD4, translocates to the nucleus, and binds to BMP-responsive elements (BRE) in the hepcidin (HAMP) promoter to induce transcription. Hepatocytes also directly sense plasma iron-TF levels by TFR1 and TFR2. Iron loading decreases TFR1 and increases TFR2 expression, favoring the displacement of HFE from TFR1 and the interaction with TFR2. HFE and TFR2 stimulate hepcidin expression via the SMAD pathway. (B) When iron availability is low, NTBI is absent and plasma iron-TF levels decrease. Low iron reduces the production of BMP ligands by endothelial cells. Sensing of low iron by hepatocytes increases TFR1 and decreases TFR2 expression, favoring the sequestration of HFE with TFR1. Iron deficiency increases expression of transmembrane serine protease 6 (TMPRSS6) which cleaves cell surface HJV, attenuating BMP signal transduction. Attenuated BMP signaling suppresses HAMP expression, promoting iron export into plasma.