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

ABSTRACT: 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.

SUBMITTER: Deshet-Unger N

PROVIDER: S-EPMC7392011 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Deshet-Unger Naamit N Kolomansky Albert A Ben-Califa Nathalie N Hiram-Bab Sahar S Gilboa Dafna D Liron Tamar T Ibrahim Maria M Awida Zamzam Z Gorodov Anton A Oster Howard S HS Mittelman Moshe M Rauner Martina M Wielockx Ben B Gabet Yankel Y Neumann Drorit D

Theranostics 20200709 19

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 pro ...[more]

PMID: 32754275

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Project description:Background: Recombinant human erythropoietin (rHuEPO), a hormone regulating the proliferation and differentiation of erythroid cells, is one of the prescription drugs used to treat cancer-associated anemia. However, administration of rHuEPO to cancer patients has been reported to be associated with decreased survival, and the mechanism by which it acts remains controversial. The present study aimed to investigate the expression of the EPO-receptor in lung cancer cell lines and whether rHuEPO treatment affected its growth and migration. Moreover, the angiogenic effects of rHuEPO were also explored in vivo. Methods: Expression of the EPO-receptor in lung cancer cell lines was measured by Western blotting and enzyme linked immunosorbent assays (ELISAs). Proliferation of the lung cancer cells was monitored in the presence of rHuEPO. Human umbilical vein endothelial cells (HUVECs) were used for tube formation assays in vitro, and transwell migration assays were performed to detect migration under rHuEPO treatment. Matrigel plug technology was employed to observe the angiogenic effects in both nude mice and Matrigel-containing lung cancer cell lines H838 or H1975. Microvessel density (MVD) was measured using CD31 Immunohistochemistry (IHC) staining. Results: EPO-receptor (EPO-R) was only detected in the cell lines H838 and H1339 by ELISA. However, the EPO-R protein was detected in all cell lines by Western blotting, which is in contradiction to the ELISA results. Proliferation and migration were not affected by rHuEPO treatment. However, rHuEPO promoted HUVEC tube formation in vitro and significantly induced the formation of new blood vessels in vivo. Furthermore, rHuEPO did not antagonize the inhibitory effects of Afatinib (epidermal growth factor receptor-tyrosine kinase inhibitor; EGFR-TKI) in simultaneous treatment with rHuEPO. In a 3D cell co-culture model, rHuEPO did not enhance the secretion of vascular endothelial growth factor (VEGF) in lung cancer cells or human lung fibroblast cell line MRC-5. Conclusions: We have shown that the role of EPO goes beyond erythropoiesis, also playing a strong role in angiogenesis by participating in new blood vessel formation in lung cancer models. Thus, rHuEPO may raise the risk of thrombosis and metastasis in vivo. Additionally, our results suggest that studies using commercially available EPO-R antibodies should be reexamined; some of these antibodies may not in fact recognize EPO-R.

Dataset Information

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

Publications

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

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