ABSTRACT
PURPOSE: Autografts, the gold standard treatment for large bone defects, present complications, especially in conditions with reduced bone-repair capacity, such as osteoporosis. Escherichia coli-derived recombinant human bone morphogenesis protein-2 (ErhBMP-2), was used in this study to improve the osteoinductivity of ß-tricalcium phosphate (ß-TCP). This study evaluated the bone-repair capacity of ErhBMP-2-loaded ß-TCP on osteoporosis rabbit model, relative to the sole use of autograft and ß-TCP treatments. METHODS: The osteoporosis rabbit model was induced through ovariectomy and glucocorticoid dosing; 2-cm segmental ulnar defects were created, which were treated with either autograft, ß-TCP alone, or ErhBMP-2-loaded ß-TCP or left untreated. The quality of newly formed ulnae was evaluated 8 weeks after ulnar surgery through micro-CT, biomechanical, histological, and histomorphometric assessments. RESULTS: The osteoporosis rabbit model was developed and maintained till the end of the study. The maximal load and stiffness in the ErhBMP-2-loaded TCP group were significantly higher than those in the autograft group, whereas the TCP-alone group performed similarly as did the untreated group in the force loading and stiffness tests. According to the micro-CT evaluation, the ErhBMP-2-loaded TCP group had significantly higher bone volume relative to the autograft and TCP-alone groups. Histological assessments revealed better defect bridging and marrow formation in the ErhBMP-2-loaded TCP group relative to the TCP-alone group. Mineral apposition rates were significantly higher in the ErhBMP-2-loaded TCP and autograft groups than in the TCP-alone and untreated groups. CONCLUSION: Relative to autografts, ErhBMP-2-loaded TCP, as an alternative grafting material, provides better or comparable healing on critical-sized long bone defects in the osteoporosis rabbit model.
ABSTRACT
Resveratrol (RVT) has various beneficial bioactivities and popularly used as a dietary supplement. RVT showed inhibitions on CYP1A2/2C9/3A4, breast cancer resistance protein (BCRP), and some conjugated metabolites of RVT also inhibited BCRP. (±)Warfarin, an anticoagulant for cardiovascular disease but with narrow therapeutic window, were substrates of CYP1A2/3A4(R-form), 2C9(S-form) and BCRP. We hypothesized that the concurrent use of RVT might affect the metabolism and excretion of warfarin. This study investigated the effect of RVT on the pharmacokinetics and anticoagulation effect of (±)warfarin. Rats were orally given (±)warfarin (0.2 mg/kg) without and with RVT (100 mg/kg) in a parallel design. The results showed that RVT significantly increased the AUC0-t of S-warfarin and international normalized ratio. Mechanism studies showed that both RVT and its serum metabolites (RSM) inhibited BCRP-mediated efflux of R- and S-warfarin. Moreover, RSM activated CYP1A2/3A4, but inhibited CYP2C9. In conclusion, concomitant intake of RVT increased the systemic exposure of warfarin and enhanced the anticoagulation effect mainly via inhibitions on BCRP and CYP2C9.
