Erythropoietin Couples Hematopoiesis with Bone Formation

Abstract

BackgroundIt is well established that bleeding activates the hematopoietic system to regenerate the loss of mature blood elements. We have shown that hematopoietic stem cells (HSCs) isolated from animals challenged with an acute bleed regulate osteoblast differentiation from marrow stromal cells. This suggests that HSCs participate in bone formation where the molecular basis for this activity is the production of BMP2 and BMP6 by HSCs. Yet, what stimulates HSCs to produce BMPs is unclear.Methodology/Principal FindingsIn this study, we demonstrate that erythropoietin (Epo) activates Jak-Stat signaling pathways in HSCs which leads to the production of BMPs. Critically, Epo also directly activates mesenchymal cells to form osteoblasts in vitro, which in vivo leads to bone formation. Importantly, Epo first activates osteoclastogenesis which is later followed by osteoblastogenesis that is induced by either Epo directly or the expression of BMPs by HSCs to form bone.Conclusions/SignificanceThese data for the first time demonstrate that Epo regulates the formation of bone by both direct and indirect pathways, and further demonstrates the exquisite coupling between hematopoesis and osteopoiesis in the marrow.

The effect of erythropoietin on bone

“…In 2008, they showed that hematopoietic stem cells (HSCs) are capable of inducing osteogenic differentiation of murine MSCs via paracrine stimulation with bone morphogenetic protein 2 and 6 (BMP-2, BMP-6) (Jung et al 2008). This finding was substantiated in a subsequent paper which demonstrated that EPO activates JAK/STAT signaling in HSCs leading to BMP secretion (Shiozawa et al 2010). In that study, daily EPO injections of 1500-6000 IU/kg for 28 days increased bone volume and the number of osteoblasts and osteoclasts in mice.…”

“…Furthermore, these authors were the first to describe a direct osteogenic effect on MSCs and osteoclasts. While EPO increased the number of osteoclasts, it impaired their function via down-regulation of cathepsin K which resulted in net bone formation (Shiozawa et al 2010;Kim et al 2012). In their setting, 20 IU/ml EPO increased the osteogenic differentiation of hMSCs about 1.7-fold compared with the positive control group estimated with alizarin red staining (AZR) after 21 days (Kim et al 2012).…”

“…EPO also stimulates multiple additional cell-based mechanisms, i.e. osteoblasts as well as hematopoietic and vascular progenitor cells (Shiozawa et al 2010;Guo et al 2012;McGee et al 2012;Rölfing et al 2012). As describe above, the applied continuous dose is the biggest challenge for in vivo trials.…”

Roles of Bone Marrow Cells in Skeletal Metastases: No Longer Bystanders

“…However, recent data demonstrated that tumor cells compete with HSCs for niche occupancy, thus the presence of HSCs can negatively regulate tumor metastasis to bone [40]. More interestingly, HSCs have been shown to increase bone morphogenetic proteins (BMP)-2 and 6 in response to erythropoietin stimuli, potentially contributing to augmented osteoblastogenesis [97]. These data collectively support that even a single cell population entity (i.e.…”

Acute hematopoietic stress in mice is followed by enhanced osteoclast maturation in the bone marrow microenvironment

“…Similarly, several studies indicated a positive correlation between enhanced erythropoiesis and osteoclastogenesis [56,58].…”