Artikel
SDF-1 alpha enhances bone regeneration induced by low dose BMP-2 in a critical size segmental bone defect
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Veröffentlicht: | 5. Oktober 2015 |
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Gliederung
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Objectives: Critical size bone defects represent a major socioeconomic problem. The growth factor bone morphogenetic protein 2 (BMP-2) is clinically established, however there has been an increasing number of clinical reports concerning severe side effects of BMP-2 used at unphysiological high local doses. In our previous study, we showed that the cytokine stromal derived factor-1 alpha (SDF-1) enhanced BMP-2 mediated bone healing.
The aim of this study was to evaluate the bone regenerative potential of BMP-2/SDF-1 functionalized biomimetic mineralized collagen type I matrix (MCM) scaffolds in a murine segmental critical size defect model in order to reduce the locally required dose of BMP-2.
Methods: Forty-four 12-week-old nu/nu nude mice were randomized to 4 groups (control group, low dose BMP-2 group, low dose BMP-2 + SDF-1 group and high dose BMP-2 group).
MCM scaffolds were functionalized with 75 mg heparin per 1 g collagen. MCM cylinders (2 mm diameter x 3 mm height) were loaded with 15 µL phosphate buffered saline containing 0, 2.5, or 15 µg rhBMP-2 and were incubated for 24 h. Additionally scaffolds for one group were loaded with a combination of 2.5 µg rhBMP-2 and 10 µg human SDF-1.
Critical size bone defects of 3 mm length were created at the right femur of each mouse and stabilized by an external fixator. Control and treatment groups received plain MCM scaffolds and MCM scaffolds loaded with BMP-2 or BMP-2 and SDF-1. After 6 weeks animals were euthanized and µCT-scans were done on each femur to analyze regenerated bone volume. For histomorphology, hematoxylin and eosin staining was performed. The degree of healing of the defect was evaluated using a scale ranging from fibrous tissue only (grade 0) to woven bone (grade 10).
Results and Conclusion: Forty-three out of 44 animals survived the surgical procedure and the observation time. The combination of low dose BMP-2 and SDF-1 (5.8±0.6 mm³, p=0.0479, unpaired t-test) as well as high dose BMP-2 (6.5±0.7 mm³, p=0.008,) significantly increased the regenerated bone volume compared to the control group (4.2±0.5 mm³). Histological analysis showed that low dose BMP-2 (mean grade 6.8±0.3, p<0.0001), low dose BMP-2 + SDF-1 (7.7±0.3, p<0.0001) and high dose BMP-2 (8.0±0.1, p<0.0001) significantly increased the degree of healing of the defect compared to the control (5.2±0.2). There were also significant differences between low dose BMP-2 and low dose BMP-2 + SDF-1 group (p<0.0296) as well as between low dose BMP-2 and high does BMP-2 group (p<0.0003).
Our study confirmed that in a critical size segmental bone defect, the osteoinductive potential of a low local concentration of BMP-2 can be significantly enhanced in the presence of SDF-1, comparable to the regenerative potential of a high BMP-2 concentration at the defect site. Combining BMP-2 and SDF-1 release from MCM scaffolds is a promising strategy to enhance bone regeneration and to avoid severe side effects of high BMP-2 doses.