Regulation of iron metabolism
Regulation of iron metabolism Unit studies the systemic iron regulation in physiologic conditions and in human disorders. The hepcidin/ferroportin axis regulates iron absorption and recycling.
The group has identified a new level of hepcidin control by the immunophilin, RNA-binding protein FKBP12, which binds to and inhibits the BMP receptor ALK2. We are exploring the FKBP12 mechanistic function, its relationship with homo and heterodimeric receptors and the effect of its liver selective inactivation.
Investigating the crosstalk between hepcidin and erythropoiesis we have defined the role of the second transferrin receptor (TFR2). Homologous to the ubiquitous TFR1, TFR2 is expressed only in hepatocytes and erythroid precursors. Hepatic TFR2 contributes to hepcidin activation and its inactivation leads to hemochromatosis. Our results suggest that TFR2 acts as a brake of EPO signaling. Erythroid TFR2, which interacts with Erythropoietin receptor (EPOR), controls the production of erythrocytes and that its bone marrow deletion causes erythropoietin-independent erythrocytosis.
The aim of current studies is to understand the molecular mechanism of TFR2-mediated hepcidin upregulation, the molecular interaction of TFR2-EPOR in erythropoiesis and to exploit the new knowledge to boost erythroid response in congenital and acquired hypoproliferative anemias and thalassemia.
Another line of investigation is focused on NCOA4, the cargo protein for ferritin degradation in the process of ferritinophagy. By transplanting bone marrow Ncoa4 null cells to wild type recipient mice and vice versa we are trying to define the contribution of NCOA4 to the physiology of erythroid and macrophage cells.
Camaschella C. Iron deficiency. Blood. 2019 Jan 3;133(1):30-39. doi: 10.1182/blood-2018-05-815944. Review
Artuso I, Lidonnici MR, Altamura S, Mandelli G, Pettinato M, Muckenthaler MU, Silvestri L, Ferrari G, Camaschella C, Nai A. Transferrin receptor 2 is a potential novel therapeutic target for β- thalassemia: evidence from a murine model. Blood. 2018 Nov 22;132(21):2286-2297.
Colucci S, Pagani A, Pettinato M, Artuso I, Nai A, Camaschella C, Silvestri L. The immunophilin FKBP12 inhibits hepcidin expression by binding the BMP type I receptor ALK2 in hepatocytes. Blood. 2017 Nov 9;130(19):2111-2120.
Nai A, Rubio A, Campanella A, Gourbeyre O, Artuso I, Bordini J, Gineste A, Latour C, Besson-Fournier C, Lin HY, Coppin H, Roth MP, Camaschella C, Silvestri L, Meynard D. Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice. Blood. 2016 May 12;127(19):2327-36.
Bordini J, Galvan S, Ponzoni M, Bertilaccio MT, Chesi M, Bergsagel PL, Camaschella C, Campanella A. Induction of iron excess restricts malignant plasma cells expansion and potentiates bortezomib effect in models of multiple myeloma. Leukemia 2017 Apr;31(4):967-970.
Camaschella C. Iron-deficiency anemia. N Engl J Med. 2015; 372:1832-1843.
Nai A, Lidonnici MR, Rausa M, Mandelli G, Pagani A, Silvestri L, Ferrari G, Camaschella C. The second transferrin receptor regulates red blood cell production in mice. Blood 2015 Feb 12;125(7):1170-9.
Hershko C, Camaschella C. How I treat unexplained refractory iron deficiency anemia. Blood 2014 Jan 16;123(3):326-33.
Camaschella C. Clinical Implication of Basic Science: Treating iron overload. NEJM. 2013; 368:2325-2327.
Nai A, Pagani A, Mandelli G, Lidonnici MR, Silvestri L, Ferrari G, Camaschella C. Deletion of TMPRSS6 attenuates the phenotype in a mouse model of beta- thalassemia. Blood 2012 May 24;119(21):5021-9.
Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of Mammalian iron metabolism. Cell 2010 Jul 9;142(1):24-38.
Nemeth E, Roetto A, Garozzo G, Ganz T, Camaschella C. Hepcidin is decreased in TFR2 haemochromatosis. Blood 2005 Feb 15;105(4):1803-6.
Roetto A, Papanikoalou G, Politou M, Alberti F, Girelli D, Christakis J, Loukopoulos D, Camaschella C. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet. 2003 Jan;33(1):21-2.
Camaschella C, Roetto A, Cali' A, De Gobbi M, Garozzo G, Carella M, Majorano N, Totaro A, Gasparini P. The gene encoding transferrin receptor 2 is mutated in a new type of hemochromatosis mapping to 7q22. Nat Genet. 2000 May;25(1):14-5.