Abstract
AbstractMutations 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.
Highlights
To determine whether BMP6, a known activator of hepcidin,[18] can modulate TMPRSS6 expression levels, Hep3B cells were treated for 16 hours with 5, 25, or 50 ng/mL of BMP6, and hepcidin and TMPRSS6 mRNA expression were measured by quantitative real-time PCR
Transfection of Hep3B cells with 5nM of siRNA TMPRSS6 reduces TMPRSS6 mRNA expression by 93% in nontreated cells and in cells treated with 25 ng/mL of BMP6 compared with Hep3B cells transfected with siRNA control
There is a complex interplay between regulatory networks that activate hepcidin expression in response to iron[14,19] and inflammation,[15] and those that inhibit hepcidin expression in response to hypoxia, anemia, and iron deficiency.[16]
Summary
The role of the BMP-SMAD signaling pathway in regulating hepcidin expression is well established.[17,18] BMP6, whose mRNA expression is regulated by iron in vivo,[19] is critical in mice to activate this signaling cascade.[20,21] BMP6 binds type I and type II BMP receptors (BMPR-I and -II) in the presence of the BMP coreceptor hemojuvelin, inducing the phosphorylation of BMPR-I by BMPR-II. The activated receptor complex, in turn, phosphorylates a subset of SMAD proteins (SMAD-1/5/8) These receptoractivated SMADs form heteromeric complexes with the common mediator SMAD4, and these translocate to the nucleus where they regulate transcription of specific targets, such as hepcidin.[22] The importance of the BMP-SMAD signaling pathway in regulating hepcidin expression and iron homeostasis in vivo is supported by the severe iron overload phenotype seen in humans and mice with mutations of genes in this pathway. Solely to indicate this fact, this article is hereby marked ‘‘advertisement’’ in accordance with 18 USC section 1734
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