Deletion of TMPRSS6 attenuates the phenotype in a mouse model of β-thalassemia

Antonella Nai, Alessia Pagani, Giacomo Mandelli, Maria Rosa Lidonnici, Laura Silvestri, Giuliana Ferrari, Clara Camaschella

Research output: Contribution to journalArticle

Abstract

Inappropriately low expression of the key iron regulator hepcidin (HAMP) causes iron overload in untransfused patients affected by β-thalassemia intermedia and Hamp modulation provides improvement of the thalassemic phenotype of the Hbb th3/+ mouse. HAMP expression is activated by iron through the bone morphogenetic protein (BMP)-son of mothers against decapentaplegic signaling pathway and inhibited by ineffective erythropoiesis through an unknown "erythroid regulator." The BMP pathway is inactivated by the serine protease TMPRSS6 that cleaves the BMP coreceptor hemojuvelin. Here, we show that homozygous loss of Tmprss6 in Hbb th3/+ mice improves anemia and reduces ineffective erythropoiesis, splenomegaly, and iron loading. All these effects are mediated by Hamp up-regulation, which inhibits iron absorption and recycling. Because Hbb th3/+ mice lacking Tmprss6 show residual ineffective erythropoiesis, our results indicate that Tmprss6 is essential for Hamp inhibition by the erythroid regulator. We also obtained partial correction of the phenotype in Tmprss6 haploinsufficient Hbb th3/+ male but not female mice and showed that the observed sex difference reflects an unequal balance between iron and erythropoiesis-mediated Hamp regulation. Our study indicates that preventing iron overload improves β-thalassemia and strengthens the essential role of Tmprss6 for Hamp suppression, providing a proof of concept that Tmprss6 manipulation can offer a novel therapeutic option in this condition.

Original languageEnglish
Pages (from-to)5021-5029
Number of pages9
JournalBlood
Volume119
Issue number21
DOIs
Publication statusPublished - May 24 2012

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Fingerprint Dive into the research topics of 'Deletion of TMPRSS6 attenuates the phenotype in a mouse model of β-thalassemia'. Together they form a unique fingerprint.

  • Cite this

    Nai, A., Pagani, A., Mandelli, G., Lidonnici, M. R., Silvestri, L., Ferrari, G., & Camaschella, C. (2012). Deletion of TMPRSS6 attenuates the phenotype in a mouse model of β-thalassemia. Blood, 119(21), 5021-5029. https://doi.org/10.1182/blood-2012-01-401885