title: Regulation of TMPRSS6 by BMP6 and iron in human cells and mice.
abstract: Mutations in transmembrane protease, serine 6 (TMPRSS6), encoding matriptase-2, are responsible for the familial anemia disorder iron-refractory iron deficiency anemia (IRIDA). Patients with IRIDA have inappropriately elevated levels of the iron regulatory hormone hepcidin, suggesting that TMPRSS6 is involved in negatively regulating hepcidin expression. Hepcidin is positively regulated by iron via the bone morphogenetic protein (BMP)-SMAD signaling pathway. In this study, we investigated whether BMP6 and iron also regulate TMPRSS6 expression. Here we demonstrate that, in vitro, treatment with BMP6 stimulates TMPRSS6 expression at the mRNA and protein levels and leads to an increase in matriptase-2 activity. Moreover, we identify that inhibitor of DNA binding 1 is the key element of the BMP-SMAD pathway to regulate TMPRSS6 expression in response to BMP6 treatment. Finally, we show that, in mice, Tmprss6 mRNA expression is stimulated by chronic iron treatment or BMP6 injection and is blocked by injection of neutralizing antibody against BMP6. Our results indicate that BMP6 and iron not only induce hepcidin expression but also induce TMPRSS6, a negative regulator of hepcidin expression. Modulation of TMPRSS6 expression could serve as a negative feedback inhibitor to avoid excessive hepcidin increases by iron to help maintain tight homeostatic balance of systemic iron levels.
authors.affiliation: Program in Membrane Biology, Division of Nephrology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Delphine
authors.initials: D
authors.lastname: Meynard
authors.forename: Valentina
authors.initials: V
authors.lastname: Vaja
authors.forename: Chia Chi
authors.initials: CC
authors.lastname: Sun
authors.forename: Elena
authors.initials: E
authors.lastname: Corradini
authors.forename: Shanzhuo
authors.initials: S
authors.lastname: Chen
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.forename: Lovorka
authors.initials: L
authors.lastname: Grgurevic
authors.forename: Charles C
authors.initials: CC
authors.lastname: Hong
authors.forename: Marit
authors.initials: M
authors.lastname: Stirnberg
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
authors.forename: Slobodan
authors.initials: S
authors.lastname: Vukicevic
authors.forename: Jodie L
authors.initials: JL
authors.lastname: Babitt
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Lin
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D055418:Bone Morphogenetic Protein 6 / Q000378:metabolism*; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D064451:Hepcidins; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008113:Liver Neoplasms; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D023181:Antimicrobial Cationic Peptides; C525816:BMP6 protein, human; C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D064451:Hepcidins; D008565:Membrane Proteins; D012333:RNA, Messenger; D007501:Iron; D052004:Bone Morphogenetic Protein Receptors; D012697:Serine Endopeptidases; C504318:TMPRSS6 protein, human; C467801:matriptase 2