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

Samuel Herberg, Cristiano Susin, Manuel Pelaez, R. Nicole Howie, Rubens Moreno De Freitas, Jaebum Lee, James J. Cray, Maribeth H. Johnson, Mohammed E. Elsalanty, Mark W. Hamrick, Carlos M. Isales, Ulf M E Wikesjö, William D. Hill

Research output: Contribution to journalArticle

47 Scopus citations

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 (0.5μg) osteoinduction in a dose-dependent order, reaching comparable levels to the optimal BMP-2 dose (5.0μg) 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.

Original languageEnglish (US)
Pages (from-to)1444-1453
Number of pages10
JournalTissue Engineering - Part A
Volume20
Issue number9-10
DOIs
StatePublished - May 1 2014

ASJC Scopus subject areas

  • Bioengineering
  • Biochemistry
  • Biomaterials
  • Biomedical Engineering

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    Herberg, S., Susin, C., Pelaez, M., Howie, R. N., Moreno De Freitas, R., Lee, J., Cray, J. J., Johnson, M. H., Elsalanty, M. E., Hamrick, M. W., Isales, C. M., Wikesjö, U. M. E., & Hill, W. D. (2014). Low-dose bone morphogenetic protein-2/stromal cell-derived factor-1β cotherapy induces bone regeneration in critical-size rat calvarial defects. Tissue Engineering - Part A, 20(9-10), 1444-1453. https://doi.org/10.1089/ten.tea.2013.0442