title: Erythropoietin promotes bone formation through EphrinB2/EphB4 signaling.
abstract: 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.
authors.affiliation: School and Hospital of Stomatology, Jilin University, Changchun, Jilin Province, China.
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.affiliation: School and Hospital of Stomatology, Jilin University, Changchun, Jilin Province, China.
authors.forename: C
authors.initials: C
authors.lastname: Shi
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, MI, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Stomatology, First People's Hospital of Chenzhou, Chenzhou, Hunan Province, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: School and Hospital of Stomatology, Jilin University, Changchun, Jilin Province, China.
authors.forename: S
authors.initials: S
authors.lastname: Ni
authors.affiliation: School and Hospital of Stomatology, Jilin University, Changchun, Jilin Province, China.
authors.forename: L
authors.initials: L
authors.lastname: Jiang
authors.affiliation: National Institute of Dental and Craniofacial Research, National Institutes of Health, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Zheng
authors.affiliation: School and Hospital of Stomatology, Jilin University, Changchun, Jilin Province, China.
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.affiliation: School and Hospital of Stomatology, Jilin University, Changchun, Jilin Province, China.
authors.forename: J
authors.initials: J
authors.lastname: Hou
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, MI, USA hcsun@mail.jlu.edu.cn rtaich@umich.edu.
authors.forename: R S
authors.initials: RS
authors.lastname: Taichman
authors.affiliation: School and Hospital of Stomatology, Jilin University, Changchun, Jilin Province, China.
authors.forename: H
authors.initials: H
authors.lastname: Sun
mesh_terms: D000539:Alveolar Process / Q000187:drug effects; D000818:Animals; D001861:Bone Regeneration / Q000187:drug effects; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D036388:Ephrin-B2 / Q000187:drug effects*; D004921:Erythropoietin / Q000494:pharmacology* / Q000627:therapeutic use; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D007180:Incisor / Q000601:surgery; D008264:Macrophages / Q000187:drug effects; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000187:drug effects; D051379:Mice; D050778:NFATC Transcription Factors / Q000187:drug effects; D010006:Osteoblasts / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D034741:RNA, Small Interfering / Q000008:administration & dosage; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D036224:Receptor, EphB4 / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D014081:Tooth Extraction; D020390:Tooth Socket / Q000187:drug effects
chemical_list: D036388:Ephrin-B2; D050778:NFATC Transcription Factors; D034741:RNA, Small Interfering; D004921:Erythropoietin; D036224:Receptor, EphB4; D020780:Matrix Metalloproteinase 9
keywords: cytokines; hematopoietic growth factors; hormones; osteoblast; osteogenesis; skeletal