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 .

Anti-CD20-Mediated B Cell Depletion Is Associated With Bone Preservation in Lymphoma Patients and Bone Mass Increase in Mice

“…This finding is in line with the lower expression of RANKL ( Figure 5B). We also found a lower frequency of B-cell-derived preosteoclasts (Figures 6B,C), defined as CD115 + /β3 integrin + Pro-B cells (23), which correlates with lower osteoclastogenic potential observed following B cell depletion ( Figure 6A).…”

“…B cells were shown to undergo trans-differentiation to macrophages (22) and these cells share similarities with osteoclast precursors (22). In this context, we have recently demonstrated B-cell-derived osteoclastogenesis both in vitro and in vivo (23). Notably, our data indicate that among BM B cells, only Pro-B cells bearing the receptor for macrophage colony-stimulating factor (MCSF-R, also known as cFms or CD115), are capable of giving rise to functional osteoclasts (23).…”

“…In this context, we have recently demonstrated B-cell-derived osteoclastogenesis both in vitro and in vivo (23). Notably, our data indicate that among BM B cells, only Pro-B cells bearing the receptor for macrophage colony-stimulating factor (MCSF-R, also known as cFms or CD115), are capable of giving rise to functional osteoclasts (23). Here, we evaluated the skeletal effects of anti-CD20 antibodies in a cohort of hematological patients with follicular lymphoma and found that this treatment is associated with a bone-preserving effect.…”

Erythropoietin in bone homeostasis—Implications for efficacious anemia therapy

“…Deshet-Unger and colleagues probed the hypothesis that osteoclasts also arise from bone marrow B cells. 22 They found that EPO enhances the ability of B cells to transdifferentiate into functional osteoclasts by upregulating the expression of known osteoclastogenic molecules such as RANKL. 22,32,33 They investigated B cell-derived osteoclastogenesis using histologi- To explore the impact of Epo-Epor signaling in B cells on bone loss, they utilized mice with conditional Epor knock-down (cKD) in the B cell lineage.…”

“…22 They found that EPO enhances the ability of B cells to transdifferentiate into functional osteoclasts by upregulating the expression of known osteoclastogenic molecules such as RANKL. 22,32,33 They investigated B cell-derived osteoclastogenesis using histologi- To explore the impact of Epo-Epor signaling in B cells on bone loss, they utilized mice with conditional Epor knock-down (cKD) in the B cell lineage. 34 Analysis of these cKD femurs by microcomputed tomography revealed an increased cortical and trabecular bone mass when compared with control mice.…”