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

Optimizing bone wound healing using BMP2 with absorbable collagen sponge and Talymed nanofiber scaffold

“…The combined scaffold did not produce better healing or more bone fill than the traditional delivery system. This outcome agrees with previous studies that found that the osteoinductive BMP2 along with an osteoconductive matrix such as ACS precipitates the greatest amount of bone growth [16, 25, 27, 31, 32]. Though we hoped that as in previous studies Talymed would precipitate denser bone growth, this did not occur when it was used with the ACS scaffold wounds [8, 9].…”

Effect of Resorbable Collagen Plug on Bone Regeneration in Rat Critical-Size Defect Model

“…35,36 Still, it is a well-established and valuable model to assess the potential of new osteoconductive biomaterials and osteoinductive regenerative strategies before pivotal evaluation in discriminating large animal models and ultimately clinical trials. [37][38][39][40][41][42][43][44][45][46][47] CONCLUSIONS Taken together, we have shown, by 3D morphometric and 2D histological analyses, RCP may be effective in the healing of extensive bone defects. In addition to its already well-accepted hemostatic property, resorbable collagen plug possesses substantial latent osteoconductive property.…”

Optimisation of BMP-2 dosage for the osseointegration of porous titanium implants in an ovine model

“…BMP-2 (Herberg et al, 2014). By the 6th week, the local concentration of BMP-2 had dropped to a level at which the balance between bone formation and bone resorption activity favoured the former process.…”

“…The induced response can, however, be readily reversed by a secondary adjustment of the dosage. BMP-2 acts osteoinductively at low (ng-to-µg) concentrations (Herberg et al, 2014), and osteolytically at high ones in the mg range (Pobloth et al, 2015). Moreover, not only the concentration, but also the mode of application and the manner in which the agent is presented to the targeted population of progenitor cells can influence their response (anabolic or catabolic), as well as their differentiation pathway.…”