Erythroferrone derived from osteoblasts regulates stress erythropoiesis.

Abstract

Erythroferrone (ERFE), secreted by erythroblasts, is regarded as a classical regulator of iron metabolism through its suppression of hepcidin. Thus, as a consequence of insufficient hepcidin suppression and reduced iron availability, global <i>Erfe</i>^-<i>^/</i>^- mice exhibit delayed recovery after phlebotomy. We have shown previously that, apart from erythroblasts, ERFE is notably expressed in osteoblasts. To explore the effect specifically of osteoblast-derived ERFE during stress erythropoiesis, we first created <i>Erfe</i>^fl/fl mice, which were then crossed with <i>Col2.3</i>-Cre mice to generate osteoblast-selective <i>Erfe</i> mutants (or <i>Col2.3</i>-Cre;<i>Erfe</i>^fl/fl mice). The induction of stress erythropoiesis in these latter mice by phlebotomy resulted in reduced serum ERFE levels and increased liver <i>Hamp</i> (hepcidin) expression. Importantly, <i>Col2.3</i>-Cre;<i>Erfe</i>^fl/fl mice showed a more robust red blood cell (RBC) recovery 6 d postphlebotomy, with no differences in bone marrow <i>Erfe</i> relative to <i>Erfe</i>^fl/fl mice. Furthermore, despite no differences in the baseline RBC count, reticulocyte count, spleen size, or bone marrow cellularity, osteoblast-selective ERFE loss resulted in enhanced erythropoietin receptor (<i>Epor</i>) and bone morphogenetic protein 4 (<i>Bmp4</i>) expression in whole bone in vivo and in osteoblasts ex vivo. Finally, the osteoblast-selective <i>Erfe</i> mutants showed erythroid lineage proliferation and enhanced EPO responsiveness in a BMP4-dependent manner. Taken together, we posit that ERFE loss specifically from osteoblasts enhances RBC recovery during stress erythropoiesis-defining mechanisms of regulation in the crosstalk between osteoblasts and erythroblasts.