Studying hepcidin and related pathways in osteoblasts using a mouse model with insulin receptor substrate 1-loss of function

Abstract

Hepcidin is one of the most important proteins in iron metabolism. In the present study, its role in iron metabolism and the associated signaling pathways involved was investigated in a mouse model with insulin receptor substrate 1-loss of function (IRS-/-), and osteoblasts in the iron overload condition. Protein expression levels of hepcidin, interleukin 6 (IL-6), bone morphogenetic protein receptor 1α and ferritin demonstrated a significant increase in the liver of the IRS-/- mice compared with the IRS+/- and IRS+/+ mice. Hepcidin levels in the jaw bone were also increased in the IRS--/- mice (although not significantly). Furthermore, mRNA expression levels of bone morphogenetic protein 6 (BMP6) and ferroportin (FPN) were significantly increased in the liver of the IRS-/- mice compared with the other two models, but no significant differences were observed in the transferrin receptor mRNA expression levels. Additionally, the mRNA expression of hepcidin, FPN and IL-6 was upregulated in osteoblasts after ferric ammonium citrate exposure, while the mRNA expression of BMP6 was inhibited. Collectively, the results of the present study indicated that hepcidin is involved in iron metabolism in IRS-1-/- mice via the signaling pathways involving BMP6 and IL-6. Furthermore, hepcidin is also involved in iron metabolism in osteoblasts under iron overload conditions. Therefore, hepcidin and its associated signaling pathway proteins may represent potential targets for the treatment of conditions associated with iron overload.