title: Low-dose bone morphogenetic protein-2/stromal cell-derived factor-1β cotherapy induces bone regeneration in critical-size rat calvarial defects.
abstract: Increasing evidence suggests that stromal cell-derived factor-1 (SDF-1/CXCL12) is involved in bone formation, though underlying molecular mechanisms remain to be fully elucidated. Also, contributions of SDF-1β, the second most abundant splice variant, as an osteogenic mediator remain obscure. We have shown that SDF-1β enhances osteogenesis by regulating bone morphogenetic protein-2 (BMP-2) signaling in vitro. Here we investigate the dose-dependent contribution of SDF-1β to suboptimal BMP-2-induced local bone formation; that is, a dose that alone would be too low to significantly induce bone formation. We utilized a critical-size rat calvarial defect model and tested the hypotheses that SDF-1β potentiates BMP-2 osteoinduction and that blocking SDF-1 signaling reduces the osteogenic potential of BMP-2 in vivo. In preliminary studies, radiographic analysis at 4 weeks postsurgery revealed a dose-dependent relationship in BMP-2-induced new bone formation. We then found that codelivery of SDF-1β potentiates suboptimal BMP-2 (0.5 μg) osteoinduction in a dose-dependent order, reaching comparable levels to the optimal BMP-2 dose (5.0 μg) without apparent adverse effects. Blocking the CXC chemokine receptor 4 (CXCR4)/SDF-1 signaling axis using AMD3100 attenuated the osteoinductive potential of the optimal BMP-2 dose, confirmed by qualitative histologic analysis. In conclusion, SDF-1β provides potent synergistic effects that support BMP-induced local bone formation and thus appears a suitable candidate for optimization of bone augmentation using significantly lower amounts of BMP-2 in spine, orthopedic, and craniofacial settings.
authors.affiliation: 1 Charlie Norwood VA Medical Center , Augusta, Georgia .
authors.forename: Samuel
authors.initials: S
authors.lastname: Herberg
authors.forename: Cristiano
authors.initials: C
authors.lastname: Susin
authors.forename: Manuel
authors.initials: M
authors.lastname: Pelaez
authors.forename: R Nicole
authors.initials: RN
authors.lastname: Howie
authors.forename: Rubens
authors.initials: R
authors.lastname: Moreno de Freitas
authors.forename: Jaebum
authors.initials: J
authors.lastname: Lee
authors.forename: James J
authors.initials: JJ
authors.lastname: Cray
authors.forename: Maribeth H
authors.initials: MH
authors.lastname: Johnson
authors.forename: Mohammed E
authors.initials: ME
authors.lastname: Elsalanty
authors.forename: Mark W
authors.initials: MW
authors.lastname: Hamrick
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Isales
authors.forename: Ulf M E
authors.initials: UM
authors.lastname: Wikesjö
authors.forename: William D
authors.initials: WD
authors.lastname: Hill
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage*; D001861:Bone Regeneration / Q000187:drug effects*; D054377:Chemokine CXCL12 / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004343:Drug Implants / Q000008:administration & dosage* / Q000737:chemistry; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012887:Skull Fractures / Q000175:diagnosis* / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D054377:Chemokine CXCL12; D004338:Drug Combinations; D004343:Drug Implants