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Bone Morphogenetic Proteins: Systems Biology Regulators pp 345–356Cite as

The Central Role of BMP Signaling in Regulating Iron Homeostasis

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Part of the book series: Progress in Inflammation Research ((PIR))

Abstract

Bone morphogenetic proteins (BMPs)/growth and differentiation factors (GDFs) are involved in a wide variety of embryologic, developmental, and physiologic processes. One important area of physiology that requires BMP signaling is the homeostatic regulation of iron in the body. Iron is an essential nutrient that is critical for several fundamental cellular processes including oxygen delivery to tissues and generation of adenosine triphosphate (ATP) in mitochondria. However, excess iron can lead to the generation of reactive oxygen species (ROS) that are highly damaging to cells, and insufficient iron is the major source of anemia worldwide. Therefore, the homeostatic regulation of total body iron content is an important physiologic process that must be exquisitely controlled to prevent the pathologic states of iron excess or iron deficiency. BMP signaling in the liver by the BMP ligands and receptors including the co-receptor hemojuvelin/RGMc regulates the expression of the iron hormone hepcidin to maintain iron homeostasis.

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References

  1. Ganz T (2013) Systemic iron homeostasis. Physiol Rev 93(4):1721–1741. doi:10.1152/physrev.00008.2013 Review

    Article  CAS  PubMed  Google Scholar 

  2. Ganz T, Nemeth E (2011) Hepcidin and disorders of iron metabolism. Annu Rev Med 62:347–360. doi:10.1146/annurev-med-050109-142444 Review

    Article  CAS  PubMed  Google Scholar 

  3. Meynard D, Babitt JL, Lin HY (2014) The liver: conductor of systemic iron balance. Blood 123(2):168–176. doi:10.1182/blood-2013-06-427757 Epub 2013 Nov 7. Review

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306(5704):2090–2093 Epub 2004 Oct 28

    Article  CAS  PubMed  Google Scholar 

  5. Verga Falzacappa MV, Vujic Spasic M, Kessler R, Stolte J, Hentze MW, Muckenthaler MU (2007) STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood 109(1):353–358 Epub 2006 Aug 31

    Article  PubMed  Google Scholar 

  6. Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, Beaumont C, Kahn A, Vaulont S (2002) The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 110:1037–1044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pietrangelo A (2004) Hereditary hemochromatosis--a new look at an old disease. N Engl J Med 350(23):2383–2397

    Article  CAS  PubMed  Google Scholar 

  8. Papanikolaou G, Samuels ME, Ludwig EH, MacDonald ML, Franchini PL, Dube MP, Andres L, MacFarlane J, Sakellaropoulos N, Politou M et al (2004) Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 36:77–82

    Article  CAS  PubMed  Google Scholar 

  9. Babitt JL, Lin HY (2011) The molecular pathogenesis of hereditary hemochromatosis. Semin Liver Dis 31(3):280–292. doi:10.1055/s-0031-1286059 Epub 2011 Sep 7. Review

    Article  CAS  PubMed  Google Scholar 

  10. Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, Campagna JA, Chung RT, Schneyer AL, Woolf CJ, Andrews NC, Lin HY (2006) Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 38(5):531–539 Epub 2006 Apr 9

    Article  CAS  PubMed  Google Scholar 

  11. Corradini E, Babitt JL, Lin HY (2009) The RGM/DRAGON family of BMP co-receptors. Cytokine Growth Factor Rev 20(5–6):389–398 Epub 2009 Nov 7. Review

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Monnier PP, Sierra A, Macchi P, Deitinghoff L, Andersen JS, Mann M, Flad M, Hornberger MR, Stahl B, Bonhoeffer F, Mueller BK (2002) RGM is a repulsive guidance molecule for retinal axons. Nature 419(6905):392–395

    Article  CAS  PubMed  Google Scholar 

  13. Samad TA, Srinivasan A, Karchewski LA, Jeong SJ, Campagna JA, Ji RR, Fabrizio DA, Zhang Y, Lin HY, Bell E, Woolf CJ (2004) DRAGON: a member of the repulsive guidance molecule-related family of neuronal- and muscle-expressed membrane proteins is regulated by DRG11 and has neuronal adhesive properties. J Neurosci 24(8):2027–2036

    Article  CAS  PubMed  Google Scholar 

  14. Samad TA, Rebbapragada A, Bell E, Zhang Y, Sidis Y, Jeong SJ, Campagna JA, Perusini S, Fabrizio DA, Schneyer AL, Lin HY, Brivanlou AH, Attisano L, Woolf CJ (2005) DRAGON, a bone morphogenetic protein co-receptor. J Biol Chem 280(14):14122–14129 Epub 2005 Jan 25

    Article  CAS  PubMed  Google Scholar 

  15. Babitt JL, Zhang Y, Samad TA, Xia Y, Tang J, Campagna JA, Schneyer AL, Woolf CJ, Lin HY (2005) Repulsive guidance molecule (RGMa), a DRAGON homologue, is a bone morphogenetic protein co-receptor. J Biol Chem 280(33):29820–29827 Epub 2005 Jun 23

    Article  CAS  PubMed  Google Scholar 

  16. Babitt JL, Huang FW, Xia Y, Sidis Y, Andrews NC, Lin HY (2007) Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest 117(7):1933–1939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Xia Y, Babitt JL, Sidis Y, Chung RT, Lin HY (2008) Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin. Blood 111(10):5195–5204. doi:10.1182/blood-2007-09-111567 Epub 2008 Mar 7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kautz L, Meynard D, Monnier A, Darnaud V, Bouvet R, Wang RH, Deng C, Vaulont S, Mosser J, Coppin H, Roth MP (2008) Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood 112(4):1503–1509. doi:10.1182/blood-2008-03-143354 Epub 2008 Jun 6

    Article  CAS  PubMed  Google Scholar 

  19. Meynard D, Kautz L, Darnaud V, Canonne-Hergaux F, Coppin H, Roth MP (2009) Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet 41(4):478–481. doi:10.1038/ng.320 Epub 2009 Mar 1

    Article  CAS  PubMed  Google Scholar 

  20. Andriopoulos B Jr, Corradini E, Xia Y, Faasse SA, Chen S, Grgurevic L, Knutson MD, Pietrangelo A, Vukicevic S, Lin HY, Babitt JL (2009) BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet 41(4):482–487. doi:10.1038/ng.335 Epub 2009 Mar 1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Daher R, Kannengiesser C, Houamel D, Lefebvre T, Bardou-Jacquet E, Ducrot N, de Kerguenec C, Jouanolle AM, Robreau AM, Oudin C, Le Gac G, Moulouel B, Loustaud-Ratti V, Bedossa P, Valla D, Gouya L, Beaumont C, Brissot P, Puy H, Karim Z, Tchernitchko D (2016) Heterozygous mutations in BMP6 pro-peptide lead to inappropriate hepcidin synthesis and moderate iron overload in humans. Gastroenterology 150(3):672–683.e4. doi:10.1053/j.gastro.2015.10.049 Epub 2015 Nov 12

    Article  CAS  PubMed  Google Scholar 

  22. Wang RH, Li C, Xu X, Zheng Y, Xiao C, Zerfas P, Cooperman S, Eckhaus M, Rouault T, Mishra L, Deng CX (2005) A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab 2(6):399–409

    Article  CAS  PubMed  Google Scholar 

  23. Mleczko-Sanecka K, Casanovas G, Ragab A, Breitkopf K, Müller A, Boutros M, Dooley S, Hentze MW, Muckenthaler MU (2010) SMAD7 controls iron metabolism as a potent inhibitor of hepcidin expression. Blood 115(13):2657–2665. doi:10.1182/blood-2009-09-238105 Epub 2009 Dec 29

    Article  CAS  PubMed  Google Scholar 

  24. Vujić Spasić M, Sparla R, Mleczko-Sanecka K, Migas MC, Breitkopf-Heinlein K, Dooley S, Vaulont S, Fleming RE, Muckenthaler MU (2013) Smad6 and Smad7 are co-regulated with hepcidin in mouse models of iron overload. Biochim Biophys Acta 1832(1):76–84. doi:10.1016/j.bbadis.2012.08.013 Epub 2012 Aug 31

    Article  PubMed  Google Scholar 

  25. Goh JB, Wallace DF, Hong W, Subramaniam VN (2015) Endofin, a novel BMP-SMAD regulator of the iron-regulatory hormone, hepcidin. Sci Rep 5:13986. doi:10.1038/srep13986

    Article  PubMed  PubMed Central  Google Scholar 

  26. Maes K, Nemeth E, Roodman GD, Huston A, Esteve F, Freytes C, Callander N, Katodritou E, Tussing-Humphreys L, Rivera S, Vanderkerken K, Lichtenstein A, Ganz T (2010) In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2. Blood 116(18):3635–3644. doi:10.1182/blood-2010-03-274571 Epub 2010 Aug 2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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 (2015) Exogenous BMP7 corrects plasma iron overload and bone loss in Bmp6−/− mice. Int Orthop 39(1):161–172. doi:10.1007/s00264-014-2550-4 Epub 2014 Oct 11

    Article  PubMed  Google Scholar 

  28. Arezes J, Jung G, Gabayan V, Valore E, Ruchala P, Gulig PA, Ganz T, Nemeth E, Bulut Y (2015) Hepcidin-induced hypoferremia is a critical host defense mechanism against the siderophilic bacterium Vibrio vulnificus. Cell Host Microbe 17(1):47–57. doi:10.1016/j.chom.2014.12.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yu PB, Hong CC, Sachidanandan C, Babitt JL, Deng DY, Hoyng SA, Lin HY, Bloch KD, Peterson RT (2008) Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol 4(1):33–41 Epub 2007 Nov 18

    Article  CAS  PubMed  Google Scholar 

  30. Silvestri L, Pagani A, Nai A, De Domenico I, Kaplan J, Camaschella C (2008) The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab 8(6):502–511. doi:10.1016/j.cmet.2008.09.012 Epub 2008 Oct 30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang CY, Meynard D, Lin HY (2014) The role of TMPRSS6/matriptase-2 in iron regulation and anemia. Front Pharmacol 5:114. doi:10.3389/fphar.2014.00114 eCollection 2014. Review

    PubMed  PubMed Central  Google Scholar 

  32. Riba M, Rausa M, Sorosina M, Cittaro D, Garcia Manteiga JM, Nai A, Pagani A, Martinelli-Boneschi F, Stupka E, Camaschella C, Silvestri L (2013) A strong anti-inflammatory signature revealed by liver transcription profiling of Tmprss6−/− mice. PLoS One 8(7):e69694. doi:10.1371/journal.pone.0069694. Print 2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Meynard D, Vaja V, Sun CC, Corradini E, Chen S, López-Otín C, Grgurevic L, Hong CC, Stirnberg M, Gütschow M, Vukicevic S, Babitt JL, Lin HY (2011) Regulation of TMPRSS6 by BMP6 and iron in human cells and mice. Blood 118(3):747–756. doi:10.1182/blood-2011-04-348698 Epub 2011 May 26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T (2014) Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet 46(7):678–684. doi:10.1038/ng.2996 Epub 2014 Jun 1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kautz L, Jung G, Nemeth E, Ganz T (2014) Erythroferrone contributes to recovery from anemia of inflammation. Blood 124(16):2569–2574. doi:10.1182/blood-2014-06-584607 Epub 2014 Sep 5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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 (2016) Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice. Blood 127(19):2327–2336. doi:10.1182/blood-2015-11-681494 Epub 2016 Jan 11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Corradini E, Garuti C, Montosi G, Ventura P, Andriopoulos B Jr, Lin HY, Pietrangelo A, Babitt JL (2009) Bone morphogenetic protein signaling is impaired in an HFE knockout mouse model of hemochromatosis. Gastroenterology 137(4):1489–1497. doi:10.1053/j.gastro.2009.06.057 Epub 2009 Jul 7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bolondi G, Garuti C, Corradini E, Zoller H, Vogel W, Finkenstedt A, Babitt JL, Lin HY, Pietrangelo A (2010) Altered hepatic BMP signaling pathway in human HFE hemochromatosis. Blood Cells Mol Dis 45(4):308–312. doi:10.1016/j.bcmd.2010.08.010 Epub 2010 Sep 21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Corradini E, Schmidt PJ, Meynard D, Garuti C, Montosi G, Chen S, Vukicevic S, Pietrangelo A, Lin HY, Babitt JL (2010) BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice. Gastroenterology 139(5):1721–1729. doi:10.1053/j.gastro.2010.07.044 Epub 2010 Aug 1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhang AS, West AP Jr, Wyman AE, Bjorkman PJ, Enns CA (2005) Interaction of hemojuvelin with neogenin results in iron accumulation in human embryonic kidney 293 cells. J Biol Chem 280(40):33885–33894 Epub 2005 Aug 15

    Article  CAS  PubMed  Google Scholar 

  41. Zhang AS, Anderson SA, Meyers KR, Hernandez C, Eisenstein RS, Enns CA (2007) Evidence that inhibition of hemojuvelin shedding in response to iron is mediated through neogenin. J Biol Chem 282(17):12547–12556 Epub 2007 Mar 1

    Article  CAS  PubMed  Google Scholar 

  42. Sun CC, Vaja V, Babitt JL, Lin HY (2012) Targeting the hepcidin-ferroportin axis to develop new treatment strategies for anemia of chronic disease and anemia of inflammation. Am J Hematol 87(4):392–400. doi:10.1002/ajh.23110 Epub 2012 Jan 31. Review

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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 (2011) Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats. Blood 118(18):4977–4984. doi:10.1182/blood-2011-03-345066 Epub 2011 Jul 5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kovac S, Böser P, Cui Y, Ferring-Appel D, Casarrubea D, Huang L, Fung E, Popp A, Mueller BK, MW H (2016) Anti-hemojuvelin antibody corrects anemia caused by inappropriately high hepcidin levels. Haematologica 101(5):e173–e176. doi:10.3324/haematol.2015.140772 Epub 2016 Mar 4. No abstract available

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

I would like to thank the members of the Division of Nephrology, Program in Membrane Biology, and Center for Systems Biology at the Massachusetts General Hospital for their continued support. This work was funded in part by NIH grant RO1DK071837. I own equity in Ferrumax sPharmaceuticals, Inc., a start-up company that has licensed technology from the Massachusetts General Hospital.

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  1. Division of Nephrology, Program in Membrane Biology, and Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA

    Herbert Y. Lin

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Correspondence to Herbert Y. Lin .

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  1. School of Medicine, University of Zagreb, Zagreb, Croatia

    Slobodan Vukicevic

  2. perForm Biologics Inc, Holliston, Massachusetts, USA

    Kuber T. Sampath

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Lin, H.Y. (2017). The Central Role of BMP Signaling in Regulating Iron Homeostasis. In: Vukicevic, S., Sampath, K. (eds) Bone Morphogenetic Proteins: Systems Biology Regulators. Progress in Inflammation Research. Springer, Cham. https://doi.org/10.1007/978-3-319-47507-3_15

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