Erythropoietin signaling in osteoblasts is required for normal bone formation and for bone loss during erythropoietin‐stimulated erythropoiesis

Suresh, Sukanya; Lee, Won Jin; Noguchi, Constance Tom

doi:10.1096/fj.202000888r

Cited by 24 publications

(22 citation statements)

References 28 publications

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“…Erythropoietin, the main hormone that stimulates erythrocyte production, has been suggested to directly and indirectly regulate bone cells (Hiram‐Bab et al, 2017; McGee et al, 2012). Epo receptor (Epor) was found on osteoblasts (Balaian et al, 2018; Suresh et al, 2020), and, consistent with previous studies (Shiozawa et al, 2010), we demonstrate that Epor is present on osteoclast precursors but is downregulated as they differentiate into osteoclasts. Epo was previously reported to directly stimulate osteoclast formation in vitro (Hiram‐Bab et al, 2015), which is consistent with our observations.…”

Section: Discussionsupporting

confidence: 91%

Active hematopoiesis triggers exosomal release of PRDX2 that promotes osteoclast formation

et al. 2021

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Hematopoietic disorders, particularly hemolytic anemias, commonly lead to bone loss. We have previously reported that actively proliferating cancer cells stimulate osteoclastogenesis from late precursors in a RANKL‐independent manner. We theorized that cancer cells exploit the physiological role of bone resorption to support expanding hematopoietic bone marrow and examined if hematopoietic cells can trigger osteoclastogenesis. Using phlebotomy‐induced acute anemia in mice, we found strong correlation between augmented erythropoiesis and increased osteoclastogenesis. Conditioned medium (CM) from K562 erythroleukemia cells and primary mouse erythroblasts stimulated osteoclastogenesis when added to RANKL‐primed precursors from mouse bone marrow or RAW264.7 cells. Using immunoblotting and mass spectrometry, PRDX2 was identified as a factor produced by erythroid cells in vitro and in vivo. PRDX2 was detected in K562‐derived exosomes, and inhibiting exosomal release significantly decreased the osteoclastogenic capacity of K562 CM. Recombinant PRDX2 induced osteoclast formation from RANKL‐primed primary or RAW 264.7 precursors to levels comparable to achieved with continuous RANKL treatment. Thus, increased bone marrow erythropoiesis secondary to anemia leads to upregulation of PRDX2, which is released in the exosomes and acts to induce osteoclast formation. Increased bone resorption by the osteoclasts expands bone marrow cavity, which likely plays a supporting role to increase blood cell production.

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Section: Discussionsupporting

confidence: 91%

Active hematopoiesis triggers exosomal release of PRDX2 that promotes osteoclast formation

et al. 2021

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“…EPO regulation of bone marrow adipocytes and skeletal bone formation is not gender specific and is mediated by Epor in bone marrow stromal cells, osteoblasts, adipocytes, and osteoclasts [21,108]. In mice, endogenous EPO is required for normal bone development and regulation of bone marrow adipocytes, while continuous EPO treatment to stimulate erythropoiesis decreases bone formation and marrow adiposity, providing implications for bone health in erythropoietic pathologies with elevated EPO such as thalassemia, sickle cell disease, and polycythemia vera [138−140].…”

Section: Discussionmentioning

confidence: 99%

“…In mice with targeted deletion of Epor in osteoblasts, trabecular bone is reduced by more than 20% by 12 weeks of age without change in the numbers of osteoblasts, osteoclasts, and marrow adipocytes, and osteogenic cultures exhibited reduced differentiation and mineralization [108]. Like DEPOR E mice, mice with osteoblast deletion of Epor manifested no additional bone loss with EPO treatment, indicating that bone loss requires a direct osteoblast EPO response and is not related to EPO-stimulated erythropoiesis [21,108]. Receptor activator of nuclear factor kB ligand (RANKL) made in osteoblasts, bone marrow stromal cells, and B and T lymphocytes contributes to bone remodeling by activating osteoclasts via binding to its receptor (RANK) to promote bone resorption [109].…”

Section: Epo Regulates Bone Marrow Stromal Cell Differentiationmentioning

confidence: 99%

Erythropoietin regulates metabolic response in mice via receptor expression in adipose tissue, brain, and bone

Noguchi

2020

Experimental Hematology

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Erythropoietin (EPO) acts by binding to erythroid progenitor cells to regulate red blood cell production. While EPO receptor (Epor) expression is highest on erythroid tissue, animal models exhibit EPO activity in nonhematopoietic tissues, mediated, in part, by tissue-specific Epor expression. This review describes the metabolic response in mice to endogenous EPO and EPO treatment associated with glucose metabolism, fat mass accumulation, and inflammation in white adipose tissue and brain during dietinduced obesity and with bone marrow fat and bone remodeling. During high-fat dietinduced obesity, EPO treatment improves glucose tolerance, decreases fat mass accumulation, and shifts white adipose tissue from a pro-inflammatory to an anti-inflammatory state. Fat mass regulation by EPO is sex dimorphic, apparent in males and abrogated by estrogen in females. Cerebral EPO also regulates fat mass and hypothalamus inflammation associated with diet-induced obesity in males and ovariectomized female mice. In bone, EPO contributes to the balance between adipogenesis and osteogenesis in both male and female mice. EPO treatment promotes bone loss mediated via Epor in osteoblasts and reduces bone marrow adipocytes before and independent of change in white adipose tissue fat mass. EPO regulation of bone loss and fat mass is independent of EPO-stimulated erythropoiesis. EPO nonhematopoietic tissue response may relate to the long-term consequences of EPO treatment of anemia in chronic kidney disease and to the alternative treatment of oral hypoxia-inducible factor prolyl hydroxylase inhibitors that increase endogenous EPO production. Published by Elsevier Inc. on behalf of ISEH -Society for Hematology and Stem Cells.Erythropoietin (EPO), produced in the kidney, is the primary regulator of erythropoiesis [1,2]. EPO is regulated by hypoxia [3]. Hypoxia-inducible factor (HIF) heterodimer (ARNT/HIF-a; primarily HIF-2a for EPO) induces EPO by binding to the EPO gene hypoxiaresponsive element [4−6]. HIF-a is stable and active under hypoxia and is targeted at normoxia by oxygendependent prolyl hydroxylase-domain (PHD) enzymes and factor-inhibiting HIF-1 [7,8]. Proline hydroxylation by PHD2 targets HIF-a for ubiquitination by Von Hippel−Lindau protein and proteasome degradation [7,9,10]. Mutations in genes for PHD2, VHL, and HIF2A, as well as EPO and EPO receptor (Epor), contribute to congenital erythrocytosis [11] and suggest alternate modalities to stimulate erythropoiesis. Recently, HIF-prolyl hydroxylase inhibitors, small molecule oral agents that stimulate production of endogenous erythropoietin, have been approved in China and Japan for treatment of anemia associated with chronic kidney disease [12,13], although adverse events with long-term administration remain unknown [14].Animal models suggest that EPO can promote a nonhematopoietic response mediated via Epor expression beyond erythroid tissue and include protection against ischemic stress and injury in brain, vascular

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“…Two recent publications have provided new insights into the contribution of endogenous Epo to bone homeostasis, and the mechanism of bone loss during EPO‐stimulated erythropoiesis. Suresh et al 21 examined the role of Epo‐Epor signaling in osteoblasts in bone formation in mice, while Deshet‐Unger et al 22 investigated the controversial topic of osteoclastogenesis arising from the transdifferentiation of B cells and the influence of EPO on this process. Both groups also studied the mechanism of bone loss caused by exogenous EPO.…”

Section: Introductionmentioning

confidence: 99%

Erythropoietin in bone homeostasis—Implications for efficacious anemia therapy

Lappin

Mills

Lappin

2021

Stem Cells Translational Medicine

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Bone homeostasis and hematopoiesis are irrevocably linked in the hypoxic environment of the bone marrow. Erythropoietin (Epo) regulates erythropoiesis by binding to its receptor, Epor, on erythroid progenitor cells. The continuous process of bone remodeling is achieved by the finely balanced activity of osteoblasts in bone synthesis and osteoclasts in bone resorption. Both osteoblasts and osteoclasts express functional Epors, but the underlying mechanism of Epo-Epor signaling in bone homeostasis is incompletely understood. Two recent publications have provided new insights into the contribution of endogenous Epo to bone homeostasis. Suresh et al examined Epo-Epor signaling in osteoblasts in bone formation in mice and Deshet-Unger et al investigated osteoclastogenesis arising from transdifferentiation of B cells. Both groups also studied bone loss in mice caused by exogenous human recombinant EPO-stimulated erythropoiesis. They found that either deletion of Epor in osteoblasts or conditional knockdown of Epor in B cells attenuates EPO-driven bone loss. These findings have direct clinical implications because patients on long-term treatment for anemia may have an increased risk of bone fractures. Phase 3 trials of small molecule inhibitors of the PHD enzymes (hypoxia inducible factor-prolyl hydroxylase inhibitors [HIF-PHIs]), such as Roxadustat, have shown improved iron metabolism and increased circulating Epo levels in a titratable manner, avoiding the supraphysiologic increases that often accompany intravenous EPO therapy. The new evidence presented by Suresh and Deshet-Unger and their colleagues on the effects of EPO-stimulated erythropoiesis on bone homeostasis seems likely to stimulate discussion on the relative merits and safety of EPO and HIF-PHIs. | INTRODUCTIONBone homeostasis is a highly organized process that requires the activity of multiple cells to coordinate bone formation and resorption.Osteoblasts, derived from mesenchymal stem cells, are responsible for bone matrix synthesis and mineralization, whereas osteoclasts derived from myeloid progenitor cells, are responsible for bone resorption. This continuous remodeling is finely balanced and is maintained by the combined action of growth factors and cytokines in the hypoxic bone marrow environment, and systemic factors such as calcitonin and estrogens. 1,2 During embryogenesis blood precursors migrate and colonize spaces created in the primitive bone marrow. 3 This close physical association provides the basis for the coordination between bone homeostasis and erythropoiesis in the bone marrow cavity that is maintained throughout adult life. The bone marrow produces

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Erythropoietin signaling in osteoblasts is required for normal bone formation and for bone loss during erythropoietin‐stimulated erythropoiesis

Cited by 24 publications

References 28 publications

Active hematopoiesis triggers exosomal release of PRDX2 that promotes osteoclast formation

Active hematopoiesis triggers exosomal release of PRDX2 that promotes osteoclast formation

Erythropoietin regulates metabolic response in mice via receptor expression in adipose tissue, brain, and bone

Erythropoietin in bone homeostasis—Implications for efficacious anemia therapy

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