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.

Regulation of TMPRSS6 by BMP6 and iron in human cells and mice / Meynard, D; Vaja, V; Sun, Cc; Corradini, Elena; Chen, Sz; Lopez Otin, C; Grgurevic, L; Hong, Cc; Stirnberg, M; Gutschow, M; Vukicevic, S; Babitt, Jl; Lin, H. Y.. - In: BLOOD. - ISSN 0006-4971. - STAMPA. - 118(3):(2011), pp. 747-756. [10.1182/blood-2011-04-348698]

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

CORRADINI, Elena;
2011

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.
2011
118(3)
747
756
Regulation of TMPRSS6 by BMP6 and iron in human cells and mice / Meynard, D; Vaja, V; Sun, Cc; Corradini, Elena; Chen, Sz; Lopez Otin, C; Grgurevic, L; Hong, Cc; Stirnberg, M; Gutschow, M; Vukicevic, S; Babitt, Jl; Lin, H. Y.. - In: BLOOD. - ISSN 0006-4971. - STAMPA. - 118(3):(2011), pp. 747-756. [10.1182/blood-2011-04-348698]
Meynard, D; Vaja, V; Sun, Cc; Corradini, Elena; Chen, Sz; Lopez Otin, C; Grgurevic, L; Hong, Cc; Stirnberg, M; Gutschow, M; Vukicevic, S; Babitt, Jl; Lin, H. Y.
File in questo prodotto:
File Dimensione Formato  
747.full.pdf

Accesso riservato

Tipologia: Versione pubblicata dall'editore
Dimensione 328.43 kB
Formato Adobe PDF
328.43 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/699308
Citazioni
  • ???jsp.display-item.citation.pmc??? 54
  • Scopus 92
  • ???jsp.display-item.citation.isi??? 88
social impact