Erythropoietin receptor in B cells plays a role in bone remodeling in mice

Naamit Deshet-Unger, Albert Kolomansky, Nathalie Ben-Califa, Sahar Hiram-Bab, Dafna Gilboa, Tamar Liron, Maria Ibrahim, Zamzam Awida, Anton Gorodov, Howard S. Oster, Moshe Mittelman, Martina Rauner, Ben Wielockx, Yankel Gabet*, Drorit Neumann*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Erythropoietin (EPO) is a key regulator of erythropoiesis. However, EPO receptors (EPO-Rs) are also expressed on non-erythroid cell types, including myeloid and bone cells. Immune cells also participate in bone homeostasis. B cells produce receptor activator of nuclear factor kappa-Β ligand (RANKL) and osteoprotegerin (OPG), two pivotal regulators of bone metabolism. Here we explored the ability of B cells to transdifferentiate into functional osteoclasts and examined the role of EPO in this process in a murine model. Methods: We have combined specifically-designed experimental mouse models and in vitro based osteoclastogenesis assays, as well as PCR analysis of gene expression. Results: (i) EPO treatment in vivo increased RANKL expression in bone marrow (BM) B cells, suggesting a paracrine effect on osteoclastogenesis; (ii) B cell-derived osteoclastogenesis occured in vivo and in vitro, as demonstrated by B cell lineage tracing in murine models; (iii) B-cell-derived osteoclastogenesis in vitro was restricted to Pro-B cells expressing CD115/CSF1-R and is enhanced by EPO; (iv) EPO treatment increased the number of B-cell-derived preosteoclasts (β3+CD115+), suggesting a physiological rationale for B cell derived osteoclastogenesis; (v) finally, mice with conditional EPO-R knockdown in the B cell lineage (cKD) displayed a higher cortical and trabecular bone mass. Moreover, cKD displayed attenuated EPO-driven trabecular bone loss, an effect that was observed despite the fact that cKD mice attained higher hemoglobin levels following EPO treatment. Conclusions: Our work highlights B cells as an important extra-erythropoietic target of EPO-EPO-R signaling and suggests their involvement in the regulation of bone homeostasis and possibly in EPO-stimulated erythropoietic response. Importantly, we present here for the first time, histological evidence for B cell-derived osteoclastogenesis in vivo.

Original languageEnglish
Pages (from-to)8744-8756
Number of pages13
Issue number19
StatePublished - 2020


  • Bone marrow
  • CFMS/CD115/CSF1R
  • Erythropoietin
  • Lymphocytes
  • Osteoclastogenesis
  • Pro-B cells
  • Transdifferentiation


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