Sunday, May 11, 2025
5/11/2025
BMP Ligands in Hepcidin Regulation - Iron is an essential nutrient, but excess iron is toxic. The master regulator of systemic iron homeostasis is the hormone hepcidin, which is secreted by the liver and induces degradation of the iron exporter ferroportin to inhibit iron absorption from the diet and iron release form body stores. Hepcidin production is regulated by iron, erythropoietic drive, and inflammation to provide adequate iron for erythropoiesis and other essential functions, but to limit the toxicity of iron excess. We have discovered that the bone morphogenetic protein (BMP) signaling pathway, via the ligands BMP6 and BMP2, is a central regulator of hepcidin transcription in response to most known signals. BMP ligands are dimeric proteins that were initially discovered as bone inducing factors, but are now known to play critical roles in many biologic processes from embryogenesis to adult tissue homeostasis in many organs. BMPs are made as inactive precursors comprised of a prodomain and a ligand domain that is released by proteolytic cleavage. Although prodomains lack signaling activity, there is increasing recognition from related BMP/TGF-b family members that prodomains play critical roles in ligand folding and dimerization, and may also regulate ligand/receptor interactions. Notably, BMP6 prodomain mutations have been linked to altered hepcidin regulation and iron overload in humans. We will show recently published data that BMP2 and BMP6 function together in hepcidin and iron homeostasis regulation; heterodimeric BMP4/7 and BMP2/7, rather than homodimeric ligands, are the major mediators mammalian embryogenesis; and BMP prodomains play essential roles in BMP4/7 heterodimer and homodimer formation and function. We therefore hypothesize that BMP2/6 heterodimers are a key functional ligand for hepcidin and iron homeostasis regulation and that prodomains have critical roles in BMP2/6 maturation and function. In Aim I, we will use our Xenopus system, primary liver cells, mouse models, and novel ELISA assay to test whether BMP2/6 heterodimers are present and regulated by iron in vivo, and to elucidate how BMP6 and BMP2 are proteolytically processed, how their prodomains contribute to heterodimer and/or homodimer formation and function to regulate hepcidin, and how BMP6 prodomain mutations impact these processes to cause iron overload. In Aim II, we will show preliminary data that both iron and erythropoietic drive still regulate hepcidin in the absence of BMP6 and/or BMP2, and we will identify two other BMP ligands that participate in hepcidin regulation. We will use genetic mouse models to establish the functional role of these two BMP ligands in hepcidin and iron homeostasis regulation in vivo. The long-term goals of this project are to understand how BMP signaling is regulated to control hepcidin expression and systemic iron homeostasis; how this process is perturbed in iron disorders such as hereditary hemochromatosis, anemia of inflammation, and b-thalassemia; and ultimately to develop new treatments for these iron disorders. We also aim to gain fundamental insights into BMP ligand maturation and prodomain function that will be relevant for many other fields where BMP signaling is important.
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