Erythropoietin Promotes Bone Formation through EphrinB2/EphB4 Signaling

• Published in: Journal of dental research 2015-03, Vol.94 (3), p.455-463
• Main Authors: Li, C., Shi, C., Kim, J., Chen, Y., Ni, S., Jiang, L., Zheng, C., Li, D., Hou, J., Taichman, R.S., Sun, H.
• Format: Article
• Language: English
• Subjects: Alveolar bone; Alveolar Process - drug effects; Animals; Bone growth; Bone marrow; Bone Regeneration - drug effects; Bone resorption; Bone turnover; Cell culture; Cell Culture Techniques; Cell differentiation; Cell Differentiation - drug effects; Cell Line; Communication; Data analysis; Dentistry; Ephrin-B2 - drug effects; Erythropoietin; Erythropoietin - pharmacology; Erythropoietin - therapeutic use; Gelatinase B; Gene Knockdown Techniques; Gene Silencing; Homeostasis; Incisor - surgery; Kinases; Ligands; Macrophages - drug effects; Male; Matrix Metalloproteinase 9 - drug effects; Mesenchymal Stromal Cells - drug effects; Mice; NFATC Transcription Factors - drug effects; Osteoblastogenesis; Osteoblasts; Osteoblasts - drug effects; Osteoclasts; Osteoclasts - drug effects; Osteogenesis; Osteogenesis - drug effects; Phenotypes; Phosphatase; Random Allocation; Rats; Rats, Wistar; Receptor, EphB4 - drug effects; Regeneration; Research Reports; RNA, Small Interfering - administration & dosage; Signal transduction; Signal Transduction - drug effects; Tooth Extraction; Tooth Socket - drug effects
• ISSN: 0022-0345; 1544-0591
• DOI: 10.1177/0022034514566431

Recent studies have demonstrated that erythropoietin (EPO) has extensive nonhematopoietic biological functions. However, little is known about how EPO regulates bone formation, although several studies suggested that EPO can affect bone homeostasis. In this study, we investigated the effects of EPO on the communication between osteoclasts and osteoblasts through the ephrinB2/EphB4 signaling pathway. We found that EPO slightly promotes osteoblastic differentiation with the increased expression of EphB4 in ST2 cells. However, EPO increased the expression of Nfatc1 and ephrinB2 but decreased the expression of Mmp9 in RAW264.7 cells, resulting in an increase of ephrinB2-expressing osteoclasts and a decrease in resorption activity. The stimulation of ephrinB2/EphB4 signaling via ephrinB2-Fc significantly promoted EPO-mediated osteoblastic differentiation in ST2 cells. EphB4 knockdown through EphB4 shRNA inhibited EPO-mediated osteoblastic phenotypes. Furthermore, in vivo assays clearly demonstrated that EPO efficiently induces new bone formation in the alveolar bone regeneration model. Taken together, these results suggest that ephrinB2/EphB4 signaling may play an important role in EPO-mediated bone formation.