Osteocyte-derived erythroferrone regulates liver hepcidin during stress erythropoiesis

Our knowledge of which bone marrow (BM) cells affect red cell production is still incomplete. To explore the role of osteocytes in the process, we performed bulk RNA sequencing of osteocytes isolated from control and phlebotomized mice. The second top upregulated gene after phlebotomy was erythroferrone (Erfe). Erfe expression in osteocytes was also upregulated after erythropoietin (EPO) treatment and hypoxia in vitro. To explore whether osteocytes contribute to systemic ERFE levels, we generated 2 mouse models. We first transplanted wild-type BM in Erfe-/- mice, creating a model where ERFE is produced in the BM but not by osteocytes. After phlebotomy, liver hepcidin suppression was significantly lower in mice where the osteocytes could not produce ERFE. To confirm that osteocytes are responsible for this difference, we generated mice lacking EPO receptors in osteocytes by crossing Eporflox/flox and Dmp1-Cre mice. After phlebotomy, these mice demonstrated reduced hepcidin suppression in the liver and higher circulating serum hepcidin levels compared with controls. Our work identified a novel function of osteocytes in suppressing systemic hepcidin levels during stress erythropoiesis.