title: Deletion of TMPRSS6 attenuates the phenotype in a mouse model of β-thalassemia.
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.
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Nai
authors.forename: Alessia
authors.initials: A
authors.lastname: Pagani
authors.forename: Giacomo
authors.initials: G
authors.lastname: Mandelli
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Lidonnici
authors.forename: Laura
authors.initials: L
authors.lastname: Silvestri
authors.forename: Giuliana
authors.initials: G
authors.lastname: Ferrari
authors.forename: Clara
authors.initials: C
authors.lastname: Camaschella
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004920:Erythropoiesis / Q000235:genetics / Q000502:physiology; D005260:Female; D017353:Gene Deletion; D064451:Hepcidins; D019190:Iron Overload / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D012697:Serine Endopeptidases / Q000235:genetics* / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics; D017086:beta-Thalassemia / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D023181:Antimicrobial Cationic Peptides; C579599:Hamp protein, mouse; D064451:Hepcidins; D008565:Membrane Proteins; D012697:Serine Endopeptidases; C467801:matriptase 2