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.

Functional role of endothelial transferrin receptor 1 in iron sensing and homeostasis

“…The BMP-SMAD pathway is the major signaling pathway responsible for regulating hepcidin transcription in response to body iron levels to provide adequate iron for erythropoiesis but limit the toxic effects of excess iron. 6 Intracellular communication between endothelial cells, as the source of BMP6 and BMP2 ligands, and hepatocytes, as the main source of hepcidin, is critical for adequate sensing of iron to control hepcidin expression and systemic iron homeostasis. However, the specific contribution of iron transporters to endothelial iron uptake and BMP ligand regulation remains poorly understood.…”

“…Hepcidin is suppressed by iron deficiency, erythropoiesis, and pregnancy to increase iron availability, 2,3 while it is induced by iron, infection, and inflammation 2,4,5 to prevent iron overload and accessibility to pathogens. Many of the signals that regulate hepcidin, including iron, act by modulating the bone morphogenetic protein (BMP)‐small mothers against decapentaplegic (SMAD) pathway 6–8 …”

“…Many of the signals that regulate hepcidin, including iron, act by modulating the bone morphogenetic protein (BMP)-small mothers against decapentaplegic (SMAD) pathway. [6][7][8] Mechanistically, iron loading induces the production of BMP6 and, to a lesser extent, BMP2, 9-12 which bind to the BMP receptor complex on hepatocytes to activate downstream SMAD signaling and induce hepcidin transcription. The induction of BMP6 and BMP2…”

Iron in Porphyrias: Friend or Foe?

“…It seems that hepatic-tissue iron content at least partially regulates hepcidin production, thereby regulating the BMP6 and BMP2 ligands syntheses, whereas serum iron induces hepcidin by activating hepatocyte 1,5,8 mothers against decapentaplegic homologs 1, 5, 8 (SMAD 1, 5, 8) signaling downstream or independent of an increase in BMP2/6 ligand [ 21 ]. Recently, nuclear factor erythroid-derived 2-like 2 (NRF2) has been linked to the above mechanism.…”

Another tool in the toolkit to manage iron overload

“…The levels of circulating hepcidin are controlled through the sensing of body iron requirements and the synthesis and release of signaling molecules from the kidney, bone marrow, immune cells, and liver sinusoidal endothelium. These systems largely impact signaling through the bone morphogenetic protein receptor and the IL-6 receptor on hepatocytes, which activate the transcription of hepcidin ( 11 ). Any impairment in these sensing or signaling systems can result in inappropriately low levels of hepcidin and inappropriately high levels of iron efflux from the gut or from cellular stores ( 12 ).…”