Journal
THERANOSTICS
Volume 10, Issue 19, Pages 8744-8756Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.45845
Keywords
bone marrow; Pro-B cells; lymphocytes; osteoclastogenesis; transdifferentiation; erythropoietin; cFMS/CD115/CSF1R
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Funding
- Schauder Memorial Endowment Fund, Sackler Faculty of Medicine, Tel Aviv University
- Israel Science Foundation (ISF) [1822/12, 343/17]
- German-Israel Foundation (GIF) [I-1433-203.12/2017]
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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-B 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 increases RANKL expression in bone marrow (BM) B cells, suggesting a paracrine effect on osteoclastogenesis; (ii) B cell-derived osteoclastogenesis occurs in vivo and in vitro, as demonstrated histologically by B cell lineage tracing in murine models, respectively; (iii) B-cell-derived osteoclastogenesis in vitro is 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 (beta 3(+)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 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 the first histological evidence for B cell-derived osteoclastogenesis in vivo.
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