Regulation of TMPRSS6 by BMP6 and iron in human cells and mice

Author:

Meynard Delphine1,Vaja Valentina12,Sun Chia Chi1,Corradini Elena13,Chen Shanzhuo1,López-Otín Carlos4,Grgurevic Lovorka5,Hong Charles C.6,Stirnberg Marit7,Gütschow Michael7,Vukicevic Slobodan5,Babitt Jodie L.1,Lin Herbert Y.1

Affiliation:

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

2. Foundation Istituto Di Ricovero e Cura a Carattere Scientifico Ca' Granda, University of Milan, Milan, Italy;

3. Center for Hemochromatosis, University Hospital of Modena and Reggio Emilia, Modena, Italy;

4. Departamento de Bioquimica y Biologia Molecular, Instituto Universitario de Oncologia, Universidad de Oviedo, Oviedo, Spain;

5. Laboratory of Mineralized Tissues, School of Medicine, University of Zagreb, Zagreb, Croatia;

6. Research Medicine, Veterans Affairs Tennessee Valley Healthcare System, Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN; and

7. Pharmaceutical Institute, University of Bonn, Bonn, Germany

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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