Novel strategies to cure hereditary hemochromatosis through modulation of the BMP/SMAD pathway regulating the iron hormone hepcidin

Hereditary hemochromatosis (HH) is the most common hereditary disease of metabolism in caucasians. It is characterized by progressive iron overload in several organs, leading to cirrhosis, diabetes, cardiomyopathy, hypogonadism and increased risk of cancer. It has been associated with mutations of at least five genes: HFE, TfR2, FPN, HJV and HAMP. The current therapy of all forms of HH is phlebotomy, however this approach requires life-long compliance, it is not always applicable, and fails to reverse established organ diseases (cirrhosis, diabetes, hypogonadism, destructive arthritis). Iron chelators may be useful, but presents limitations and adverse effects. Therefore there is a strong need for developing new tools to prevent/remove iron excess in HH. Recent research developments offer now important clues for the cure of HH. Regardless of the underlying genetic defect, all forms of HH appear to be due to a defective synthesis of the iron hormone, hepcidin. Each HH protein plays a role in the regulation of hepcidin, but the details of these process are still unclear. Interestingly, preliminary data from our lab indicate that administration of BMP6, a key regulator of hepcidin, can bypass the need for HFE and enhance hepcidin expression in HFE-KO mice. This suggests that BMPs-like agonists may be an alternative treatment strategy for managing iron overload in HH. The overall objective of this project is to develop novel strategies for the cure of HH by rescuing the defective expression of the iron hormone hepcidin. Specifically, we will study how iron regulates hepcidin through the BMPs, the expression of BMPs, particularly BMP6, in human HH and, finally, we will study if and how exogenous BMPs can prevent or reverse in vivo the disease phenotype in a mouse model of HH (Hfe-Knock out mice). We believe this project will enhance our understanding of the role and regulation of BMP and hepcidin in HH and will offer new clues on development of alternative and/or complementary pharmacological intervention to cure HH and other iron-overload disorders associated with hepcidin deficiency.