
Babitt, Jodie, MD
Associate ProfessorMy laboratory is focused on elucidating the molecular and cellular mechanisms involved in iron homeostasis. Our ultimate goal is to identify new treatment strategies for disorders of iron homeostasis, such as the anemia of chronic disease and the iron overload disorder hemochromatosis.
Based on its ability to donate and accept electrons, iron is essential for many biological reactions important for living organisms including oxygen transport, cellular respiration, and DNA synthesis. However, this same property makes excess iron toxic by generating free radicals that can damage lipid membranes, proteins, and nucleic acids leading to cell death. As a result, iron levels must be tightly regulated both on a cellular level and systemically.
We have recently discovered that the bone morphogenetic protein (BMP) signaling pathway plays an important role in systemic iron balance by modulating expression of the main iron regulatory hormone hepcidin. A soluble protein secreted by the liver, hepcidin works by blocking the iron channel ferroportin, preventing iron release into the bloodstream from dietary sources and from iron storage cells. Hepcidin expression is induced by inflammation, which is thought to be part of the host defense mechanism to fight infection and cancer by limiting iron availability. However, in chronic inflammatory states, this leads to a deficiency of iron available for red blood cell production, and this is thought be one mechanism underlying the anemia of chronic disease. In contrast, hepcidin deficiency, which causes excessive dietary iron absorption and progressive tissue iron deposition and dysfunction, appears to be the common pathogenic mechanism underlying the iron overload disorder hereditary hemochromatosis.
Our lab has recently shown that 1) mutations in either the BMP co-receptor hemojuvelin or BMP6 ligand each lead to hepcidin deficiency and severe hemochromatosis; 2) iron regulates BMP ligand expression and BMP signal transduction in the liver; and 3) modulation of the BMP signaling pathway in vivo regulates hepcidin expression and systemic iron balance. Our current focus is working to understand the molecular and cellular mechanisms by which body iron levels are sensed and how this signal is transduced to modulate hepcidin expression and maintain systemic iron balance. We are also testing BMP-hepcidin pathway modulators as new treatment strategies for anemia of chronic disease and hemochromatosis.
Publications
Wang CY, Xu Y, Traeger L, Dogan DY, Xiao X, Steinbicker AU, Babitt JL Erythroferrone lowers hepcidin by sequestering BMP2/6 heterodimer from binding to the BMP type I receptor ALK3. Blood. 2020;135(6):453-456 - PMID: 31800957 - PMCID: PMC7005366 - DOI: 10.1182/blood.2019002620
Xiao X, Dev S, Canali S, Bayer A, Xu Y, Agarwal A, Wang CY, Babitt JL Endothelial Bmp2 knockout exacerbates hemochromatosis in Hfe knockout mice but not Bmp6 knockout mice. Hepatology. 2020;72(2):642-655 - PMID: 31778583 - PMCID: PMC7253321 - DOI: 10.1002/hep.31048
Lim PJ, Duarte TL, Arezes J, Garcia-Santos D, Hamdi A, Pasricha SR, Armitage AE, Mehta H, Wideman S, Santos AG, Santos-Gonçalves A, Morovat A, Hughes JR, Soilleux E, Wang CY, Bayer AL, Klenerman P, Willberg CB, Hartley RC, Murphy MP, Babitt JL, Ponka P, Porto G, Drakesmith H Nrf2 controls iron homeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin. Nat Metab. 2019;1(5):519-531 - PMID: 31276102 - PMCID: PMC6609153 - DOI: 10.1038/s42255-019-0063-6
Babitt JL Ironing out pulmonary arterial hypertension. Proc Natl Acad Sci U S A. 2019;116(26):12604-12606 - PMID: 31171658 - PMCID: PMC6601273 - DOI: 10.1073/pnas.1908298116
Babitt JL, Sitara D Crosstalk between fibroblast growth factor 23, iron, erythropoietin, and inflammation in kidney disease. Curr Opin Nephrol Hypertens. 2019;28(4):304-310 - PMID: 31145704 - PMCID: PMC6693648 - DOI: 10.1097/MNH.0000000000000514
Wang CY, Xiao X, Bayer A, Xu Y, Dev S, Canali S, Nair AV, Masia R, Babitt JL Ablation of hepatocyte Smad1, Smad5 and Smad8 causes severe tissue iron loading and liver fibrosis in mice. Hepatology. 2019;70(6):1986-2002 - PMID: 31127639 - PMCID: PMC6874904 - DOI: 10.1002/hep.30780
Leaf DE, Rajapurkar M, Lele SS, Mukhopadhyay B, Boerger EAS, Mc Causland FR, Eisenga MF, Singh K, Babitt JL, Kellum JA, Palevsky PM, Christov M, Waikar SS Iron, Hepcidin, and Death in Human AKI. J Am Soc Nephrol. 2019;30(3):493-504 - PMID: 30737269 - PMCID: PMC6405140 - DOI: 10.1681/ASN.2018100979
Eddowes LA, Al-Hourani K, Ramamurthy N, Frankish J, Baddock HT, Sandor C, Ryan JD, Fusco DN, Arezes J, Giannoulatou E, Boninsegna S, Chevaliez S, Owens BMJ, Sun CC, Fabris P, Giordani MT, Martines D, Vukicevic S, Crowe J, Lin HY, Rehwinkel J, McHugh PJ, Binder M, Babitt JL, Chung RT, Lawless MW, Armitage AE, Webber C, Klenerman P, Drakesmith H Antiviral activity of bone morphogenetic proteins and activins. Nat Microbiol. 2019;4(2):339-351 - PMID: 30510168 - PMCID: PMC6590058 - DOI: 10.1038/s41564-018-0301-9
Wang CY, Canali S, Bayer A, Dev S, Agarwal A, Babitt JL Iron, erythropoietin, and inflammation regulate hepcidin in Bmp2-deficient mice, but serum iron fails to induce hepcidin in Bmp6-deficient mice. Am J Hematol. 2019;94(2):240-248 - PMID: 30478858 - PMCID: PMC6492930 - DOI: 10.1002/ajh.25366
Wang CY, Babitt JL Liver iron sensing and body iron homeostasis. Blood. 2019;133(1):18-29 - PMID: 30401708 - PMCID: PMC6318427 - DOI: 10.1182/blood-2018-06-815894
He Q, Bouley R, Liu Z, Wein MN, Zhu Y, Spatz JM, Wang CY, Divieti Pajevic P, Plagge A, Babitt JL, Bastepe M Large G protein α-subunit XLαs limits clathrin-mediated endocytosis and regulates tissue iron levels in vivo. Proc Natl Acad Sci U S A. 2017;114(45):E9559-E9568 - PMID: 29078380 - PMCID: PMC5692581 - DOI: 10.1073/pnas.1712670114
Canali S, Wang CY, Zumbrennen-Bullough KB, Bayer A, Babitt JL Bmp2 controls iron homeostasis in mice independent of Bmp6. Am J Hematol. 2017;92(11):1204-1213 - PMID: 28815688 - PMCID: PMC5986189 - DOI: 10.1002/ajh.24888
Wang CY, Core AB, Canali S, Zumbrennen-Bullough KB, Ozer S, Umans L, Zwijsen A, Babitt JL Smad1/5 is required for erythropoietin-mediated suppression of hepcidin in mice. Blood. 2017;130(1):73-83 - PMID: 28438754 - PMCID: PMC5501149 - DOI: 10.1182/blood-2016-12-759423
Dev S, Babitt JL Overview of iron metabolism in health and disease. Hemodial Int. 2017;21 Suppl 1:S6-S20 - PMID: 28296010 - PMCID: PMC5977983 - DOI: 10.1111/hdi.12542
Canali S, Zumbrennen-Bullough KB, Core AB, Wang CY, Nairz M, Bouley R, Swirski FK, Babitt JL Endothelial cells produce bone morphogenetic protein 6 required for iron homeostasis in mice. Blood. 2017;129(4):405-414 - PMID: 27864295 - PMCID: PMC5270389 - DOI: 10.1182/blood-2016-06-721571
David V, Francis C, Babitt JL Ironing out the crosstalk between FGF23 and inflammation. Am J Physiol Renal Physiol. 2017;312(1):F1-F8 - PMID: 27582104 - PMCID: PMC5283889 - DOI: 10.1152/ajprenal.00359.2016
Sise ME, Wisocky J, Rosales IA, Chute D, Holmes JA, Corapi KM, Babitt JL, Tangren JS, Hashemi N, Lundquist AL, Williams WW, Mount DB, Andersson KL, Rennke HG, Smith RN, Colvin R, Thadhani RI, Chung RT Lupus-like Immune Complex-mediated Glomerulonephritis in Patients with Hepatitis C Virus Infection Treated with Oral, Interferon-free, Direct-acting Antiviral Therapy. Kidney Int. 2016;1(3):135-143 - PMID: 27990496 - PMCID: PMC5155703 - DOI: 10.1016/j.ekir.2016.06.006
Canali S, Vecchi C, Garuti C, Montosi G, Babitt JL, Pietrangelo A The SMAD pathway is required for hepcidin response during endoplasmic reticulum stress. Endocrinology. 2016;157(10):3935-3945 - PMID: 27483343 - PMCID: PMC5045507 - DOI: 10.1210/en.2016-1258
Theurl I, Hilgendorf I, Nairz M, Tymoszuk P, Haschka D, Asshoff M, He S, Gerhardt LM, Holderried TA, Seifert M, Sopper S, Fenn AM, Anzai A, Rattik S, McAlpine C, Theurl M, Wieghofer P, Iwamoto Y, Weber GF, Harder NK, Chousterman BG, Arvedson TL, McKee M, Wang F, Lutz OM, Rezoagli E, Babitt JL, Berra L, Prinz M, Nahrendorf M, Weiss G, Weissleder R, Lin HY, Swirski FK On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver. Nature Med. 2016;22(8):945-951 - PMID: 27428900 - PMCID: PMC4957133 - DOI: 10.1038/nm.4146
Wang CY, Babitt JL Hepcidin regulation in the anemia of inflammation. Curr Opin Hematol. 2016;23(3):189-197 - PMID: 26886082 - PMCID: PMC4993159 - DOI: 10.1097/MOH.0000000000000236
Canali S, Core AB, Zumbrennen-Bullough KB, Merkulova M, Wang CY, Schneyer A, Pietrangelo A, Babitt JL Activin B induces noncanonical SMAD1/5/8 signaling via BMP type I receptors in hepatocytes: evidence for a role in hepcidin induction by inflammation in male mice. Endocrinology. 2016;157(3):1146-62 - PMID: 26735394 - PMCID: PMC4769363 - DOI: 10.1210/en.2015-1747
David V, Martin A, Isakova T, Spaulding C, Qi L, Ramirez V, Zumbrennen-Bullough KB, Sun CC, Lin HY, Babitt JL, Wolf M Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int. 2016;89(1):135-46 - PMID: 26535997 - PMCID: PMC4854810 - DOI: 10.1038/ki.2015.290
Samir AE, Allegretti AS, Zhu Q, Dhyani M, Anvari A, Sullivan DA, Trottier CA, Dougherty S, Williams WW, Babitt JL, Wenger J, Thadhani RI, Lin HY Shear wave elastography in chronic kidney disease: a pilot experience in native kidneys. BMC Nephrol. 2015;16(1):119 - PMID: 26227484 - PMCID: PMC4521488 - DOI: 10.1186/s12882-015-0120-7
Tesfay L, Clausen KA, Kim JW, Hedge P, Wang X, Miller LD, Deng Z, Blanchette N, Arvedson T, Miranti CK, Babitt JL, Lin HY, Peehl DM, Torti FM, Torti SV Hepcidin regulation in prostate and its disruption in prostate cancer. Cancer Res. 2015;75(11):2254-63 - PMID: 25858146 - PMCID: PMC4454355 - DOI: 10.1158/0008-5472.CAN-14-2465
Pauk M, Grgurevic L, Brkljacic J, Kufner V, Bordukalo-Niksic T, Grabusic K, Razdorov G, Rogic D, Zuvic M, Oppermann H, Babitt JL, Lin HY, Volarevic S, Vukicevic S Exogenous BMP7 corrects plasma iron overload and bone loss in Bmp6-/- mice. Int Orthop. 2015;39(1):161-172 - PMID: 25300398 - DOI: 10.1007/s00264-014-2550-4
Zumbrennen-Bullough K, Wu Q, Core AB, Canali S, Chen W, Theurl I, Meynard D, Babitt JL MicroRNA-130a is upregulated in mouse liver by iron deficiency and targets the bone morphogenetic protein (BMP) receptor ALK2 to attenuate BMP signaling and hepcidin transcription. J Biol Chem. 2014;289(34):23796-808 - PMID: 25002578 - PMCID: PMC4156078 - DOI: 10.1074/jbc.M114.577387
Core AB, Canali S, Babitt JL Hemojuvelin and bone morphogenetic protein (BMP) signaling in iron homeostasis. Front Pharmacol. 2014;5:104 - PMID: 24860505 - PMCID: PMC4026703 - DOI: 10.3389/fphar.2014.00104
Babitt JL, Lin HY BuMPing iron with modified heparins. Blood. 2014;123(10):1440-1 - PMID: 24627550 - PMCID: PMC3945857 - DOI: 10.1182/blood-2014-01-549519
Zumbrennen-Bullough K, Babitt JL The iron cycle in CKD: from genetics and experimental models to CKD patients. Nephrol Dial Transplant. 2014;29(2):263-73 - PMID: 24235084 - PMCID: PMC3910345 - DOI: 10.1093/ndt/gft443
Meynard D, Babitt JL, Lin HY The liver: conductor of systemic iron regulation. Blood. 2014;123(2):168-76 - PMID: 24200681 - PMCID: PMC3888285 - DOI: 10.1182/blood-2013-06-427757
Meynard D, Sun CC, Wu Q, Chen W, Chen S, Nelson CN, Waters MJ, Babitt JL, Lin HY Inflammation Regulates TMPRSS6 Expression via STAT5. PLoS ONE. 2013;8(12):e82127 - PMID: 24376517 - PMCID: PMC3871639 - DOI: 10.1371/journal.pone.0082127
Sun CC, Vaja V, Chen S, Theurl I, Stepanek A, Brown DE, Cappellini MD, Weiss G, Hong CC, Lin HY, Babitt JL A hepcidin lowering agent mobilizes iron for incorporation into red blood cells in an adenine-induced kidney disease model of anemia in rats. Nephrol Dial Transplant. 2013;28(7):1733-1743 - PMID: 23345622 - PMCID: PMC3707526 - DOI: 10.1093/ndt/gfs584
Bouley R, Nunes P, Andriopoulos B, McLaughlin MM, Webber MJ, Lin HY, Babitt JL, Gardella TJ, Ausiello DA, Brown D Heterologous downregulation of vasopressin type 2 receptor is induced by transferrin. Am J Physiol Renal Physiol. 2013;304(5):F553-64 - PMID: 23235478 - PMCID: PMC3602717 - DOI: 10.1152/ajprenal.00438.2011
Chen W, Sun CC, Chen S, Meynard D, Babitt JL, Lin HY A novel validated enzyme-linked immunosorbent assay to quantify soluble hemojuvelin in mouse serum. Haematologica. 2013;98(2):296-304 - PMID: 22875629 - PMCID: PMC3561439 - DOI: 10.3324/haematol.2012.070136
Wu X, Yung LM, Cheng WH, Yu PB, Babitt JL, Lin HY, Xia Y Hepcidin Regulation by BMP Signaling in Macrophages Is Lipopolysaccharide Dependent. PLoS ONE. 2012;7(9):e44622 - PMID: 23028567 - PMCID: PMC3441567 - DOI: 10.1371/journal.pone.0044622
Wu Q, Sun CC, Lin HY, Babitt JL Repulsive Guidance Molecule (RGM) Family Proteins Exhibit Differential Binding Kinetics for Bone Morphogenetic Proteins (BMPs). PLoS ONE. 2012;7(9):e46307 - PMID: 23029472 - PMCID: PMC3459908 - DOI: 10.1371/journal.pone.0046307
Gutiérrez OM, Sun CC, Chen W, Babitt JL, Lin HY Statement of Concern about a Commercial Assay Used to Measure Soluble Hemojuvelin in Humans. Am J Nephrol. 2012;36(4):332-333 - PMID: 23006450 - DOI: 10.1159/000342519
Babitt JL, Lin HY Mechanisms of Anemia in CKD. J Am Soc Nephrol. 2012;23(10):1631-4 - PMID: 22935483 - PMCID: PMC3458456 - DOI: 10.1681/ASN.2011111078
Sun CC, Vaja V, Babitt JL, Lin HY Targeting the hepcidin-ferroportin axis to develop new treatment strategies for anemia of chronic disease and anemia of inflammation. Am J Hematol. 2012;87(4):392-400 - PMID: 22290531 - PMCID: PMC3653431 - DOI: 10.1002/ajh.23110
Wang L, Trebicka E, Fu Y, Ellenbogen S, Hong CC, Babitt JL, Lin HY, Cherayil BJ The bone morphogenetic protein-hepcidin axis as a therapeutic target in inflammatory bowel disease. Inflamm Bowel Dis. 2012;18(1):112-9 - PMID: 21351217 - PMCID: PMC3139830 - DOI: 10.1002/ibd.21675
Babitt JL, Lin HY The molecular pathogenesis of hereditary hemochromatosis. Semin Liver Dis. 2011;31(3):280-92 - PMID: 21901658 - DOI: 10.1055/s-0031-1286059
Corradini E, Rozier M, Meynard D, Odhiambo A, Lin HY, Feng Q, Migas MC, Britton RS, Babitt JL, Fleming RE Iron regulation of hepcidin despite attenuated Smad1,5,8 signaling in mice without transferrin receptor 2 or Hfe. Gastroenterology. 2011;141(5):1907-14 - PMID: 21745449 - PMCID: PMC3634343 - DOI: 10.1053/j.gastro.2011.06.077
Theurl I, Schroll A, Sonnweber T, Nairz M, Theurl M, Willenbacher W, Eller K, Wolf D, Seifert M, Sun CC, Babitt JL, Hong CC, Menhall T, Gearing P, Lin HY, Weiss G Pharmacologic inhibition of hepcidin expression reverses anemia of chronic disease in rats. Blood. 2011;118(18):4977-84 - PMID: 21730356 - PMCID: PMC3208302 - DOI: 10.1182/blood-2011-03-345066
Meynard D, Vaja V, Sun CC, Corradini E, Chen S, Lopez-Otin C, Grgurevic L, Hong CC, Stirnberg M, Gutschow M, Vukicevic S, Babitt JL, Lin HY Regulation of TMPRSS6 by BMP6 and iron in human cells and mice. Blood. 2011;118(3):747-56 - PMID: 21622652 - PMCID: PMC3142910 - DOI: 10.1182/blood-2011-04-348698
Corradini E, Meynard D, Wu Q, Chen S, Ventura P, Pietrangelo A, Babitt JL Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway in mice. Hepatology. 2011;54(1):273-84 - PMID: 21488083 - PMCID: PMC3277401 - DOI: 10.1002/hep.24359
Gibert Y, Lattanzi VJ, Zhen AW, Vedder L, Brunet F, Faasse SA, Babitt JL, Lin HY, Hammerschmidt M, Fraenkel PG BMP Signaling Modulates Hepcidin Expression in Zebrafish Embryos Independent of Hemojuvelin. PLoS ONE. 2011;6(1):e14553 - PMID: 21283739 - PMCID: PMC3024971 - DOI: 10.1371/journal.pone.0014553
Bolondi G, Garuti C, Corradini E, Zoller H, Vogel W, Finkenstedt A, Babitt JL, Lin HY, Pietrangelo A Altered hepatic BMP signaling pathway in human HFE hemochromatosis. Blood Cells Mol Dis. 2010;45(4):308-12 - PMID: 20863724 - PMCID: PMC3295241 - DOI: 10.1016/j.bcmd.2010.08.010
Corradini E, Schmidt PJ, Meynard D, Garuti C, Montosi G, Chen S, Vukicevic S, Pietrangelo A, Lin HY, Babitt JL BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice. Gastroenterology. 2010;139(5):1721-9 - PMID: 20682319 - PMCID: PMC3295242 - DOI: 10.1053/j.gastro.2010.07.044
Babitt JL, Lin HY Molecular Mechanisms of Hepcidin Regulation: Implications for the Anemia of CKD. Am J Kidney Dis. 2010;55(4):726-41 - PMID: 20189278 - PMCID: PMC2905036 - DOI: 10.1053/j.ajkd.2009.12.030
Xia Y, Babitt JL, Bouley R, Zhang Y, Silva ND, Chen S, Zhuang Z, Samad TA, Brenner GJ, Anderson JL, Hong CC, Schneyer AL, Brown D, Lin HY Dragon Enhances BMP Signaling and Increases Transepithelial Resistance in Kidney Epithelial Cells. J Am Soc Nephrol. 2010;21(4):666-77 - PMID: 20167703 - PMCID: PMC2844302 - DOI: 10.1681/ASN.2009050511
Corradini E, Babitt JL, Lin HY The RGM/DRAGON family of BMP co-receptors. Cytokine Growth Factor Rev. 2009;20(5-6):389-98 - PMID: 19897400 - PMCID: PMC3715994 - DOI: 10.1016/j.cytogfr.2009.10.008
Wang L, Harrington L, Trebicka E, Shi HN, Kagan JC, Hong CC, Lin HY, Babitt JL, Cherayil BJ Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice. J Clin Invest. 2009;119(11):3322-8 - PMID: 19809161 - PMCID: PMC2769199 - DOI: 10.1172/JCI39939
Corradini E, Garuti C, Montosi G, Ventura P, Andriopoulos B, Lin HY, Pietrangelo A, Babitt JL Bone morphogenetic protein signaling is impaired in an Hfe knockout mouse model of hemochromatosis. Gastroenterology. 2009;137(4):1489-97 - PMID: 19591830 - PMCID: PMC2757523 - DOI: 10.1053/j.gastro.2009.06.057
Andriopoulos Jr B, Corradini E, Xia Y, Faasse SA, Chen S, Grgurevic L, Knutson MD, Pietrangelo A, Vukicevic S, Lin HY, Babitt JL BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet. 2009;41(4):482-7 - PMID: 19252486 - PMCID: PMC2810136 - DOI: 10.1038/ng.335
Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, Campagna JA, Chung RT, Schneyer AL, Woolf CJ, Andrews NC, Lin HY Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006;38(5):531-9 - PMID: 16604073 - DOI: 10.1038/ng1777
Babitt J, Zhang Y, Samad T, Xia Y, Tang J, Campagna J, Schneyer A, Woolf C, Lin HY Repulsive guidance molecule (RGMa), a DRAGON homologue, is a bone morphogenetic protein co-receptor. J Biol Chem. 2005;280(33):29820-7 - PMID: 15975920 - DOI: 10.1074/jbc.M503511200
del Re E, Babitt J, Pirani A, Schneyer A, Lin HY In the absence of type III receptor, the transforming growth factor (TGF)-beta type II-B receptor requires the type I receptor to bind TGF-beta2. J Biol Chem. 2004;279(21):22765-72 - PMID: 14996829 - DOI: 10.1074/jbc.M401350200