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Low-dose bone morphogenetic protein-2/stromal cell-derived factor-1? 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-1?, the second most abundant splice variant, as an osteogenic mediator remain obscure. We have shown that SDF-1? enhances osteogenesis by regulating bone morphogenetic protein-2 (BMP-2) signaling in vitro. Here we investigate the dose-dependent contribution of SDF-1? 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-1? 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-1? potentiates suboptimal BMP-2 (0.5??g) osteoinduction in a dose-dependent order, reaching comparable levels to the optimal BMP-2 dose (5.0??g) 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-1? 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.

SUBMITTER: Herberg S 

PROVIDER: S-EPMC4012411 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Low-dose bone morphogenetic protein-2/stromal cell-derived factor-1β cotherapy induces bone regeneration in critical-size rat calvarial defects.

Herberg Samuel S   Susin Cristiano C   Pelaez Manuel M   Howie R Nicole RN   Moreno de Freitas Rubens R   Lee Jaebum J   Cray James J JJ   Johnson Maribeth H MH   Elsalanty Mohammed E ME   Hamrick Mark W MW   Isales Carlos M CM   Wikesjö Ulf M E UM   Hill William D WD  

Tissue engineering. Part A 20140219 9-10


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-induc  ...[more]

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