Erythropoietin Modulates the Structure of Bone Morphogenetic Protein 2–Engineered Cranial Bone

Abstract

The ideally engineered bone should have similar structural and functional properties to the native tissue. Although structural integrity is critical for functional bone regeneration, we know less about modulating the structural properties of the engineered bone elicited by bone morphogenetic protein (BMP) than efficacy and safety. Erythropoietin (Epo), a primary erythropoietic hormone, has been used to augment blood transfusion in orthopedic surgery. However, the effects of Epo on bone regeneration are not well known. Here, we determined the role of Epo in BMP2-induced bone regeneration using a cranial defect model. Epo administration improved the quality of BMP2-induced bone and more closely resembled natural cranial bone with a higher bone volume (BV) fraction and lower marrow fraction when compared with BMP2 treatment alone. Epo increased red blood cells (RBCs) in peripheral blood and also increased hematopoietic and mesenchymal stem cell (MSC) populations in bone marrow. Consistent with our previous work, Epo increased osteoclastogenesis both in vitro and in vivo. Results from a metatarsal organ culture assay suggested that Epo-promoted osteoclastogenesis contributed to angiogenesis because angiogenesis was blunted when osteoclastogenesis was blocked by alendronate (ALN) or osteoprotegerin (OPG). Earlier calcification of BMP2-induced temporary chondroid tissue was observed in the Epo + BMP group compared to BMP2 alone. We conclude that Epo significantly enhanced the outcomes of BMP2-induced cranial bone regeneration in part through its actions on osteoclastogenesis and angiogenesis.

Erythropoietin Promotes Bone Formation through EphrinB2/EphB4 Signaling

“…The effects of EPO on bone homeostasis, however, remain controversial Singbrant et al 2011;Kim et al 2012;McGee et al 2012;Sun et al 2012). Herein, we investigated the role of EPO-mediated differentiation of osteoblasts and osteoclasts on their communication through ephrinB2/EphB4 signaling in vitro and in an in vivo wound model.…”

Whole extracts of Radix Achyranthis Bidentatae and Radix Cyathulae promote angiogenesis in human umbilical vein endothelial cells in vitro and in zebrafish in vivo

“…For example, physiological angiogenesis always occurs in the endometrium during the menstrual cycle, and appears in the basalis layer during menstruation and in the functionalis and subepithelial capillary plexus during the proliferative and early secretory stages (3). In addition, it is well-known that blood vessel formation is associated in bone regeneration (23). During bone fracture healing, ingrowth of blood vessels are responsible for supplying nutrients and the influx of osteoblasts (24).…”

Dual Delivery of EPO and BMP2 from a Novel Modular Poly-ɛ-Caprolactone Construct to Increase the Bone Formation in Prefabricated Bone Flaps

“…After 6 weeks, the dual delivery group had a higher BV fraction than the BMP2 alone group. 28 There is limited to no knowledge of the binding and release of adsorbed EPO on PCL and, furthermore, the effect of dual EPO and BMP2 delivery on bone regenerated in an ectopic location for the application of prefabricated flaps is unknown.…”

“…EPO has shown to play a role in osteoclastogenesis and osteoclasts can recruit mesenchymal stem cells to the site of bone remodeling. 28 If EPO caused an initial increase in osteoclast numbers, this may have resulted in increased bone-forming cells recruited to the construct. Interestingly, although dual delivery had more bone than the BMP2 group, the BMP2 group had a higher TMD when compared with BMP2 + EPO at both time points.…”

“…Kobayashi et al delivered EPO using a gelatin hydrogel at the surface of a rabbit heart, 26 and Chen et al delivered EPO using fibrin gel to increase neovascularization. 27 Interactions between EPO and BMP2 have been studied in vitro 19,20 and in vivo, 28,29 and results have shown synergistic effects on bone formation.…”