engleski

BMP-1 ENHANCES BONE REPAIR IN FRACTURE MODELS

Aim: Bone fracture repair is often limited and unpredictive due to limited organism regenerative potential and xenograft scaffolds currently in use. During first stages of fracture coagulum formation is essential for successful repair. At later stages of fracture repair normal extracellular matrix (ECM) deposition is required for creating a scaffold for bone mineralization. BMP1 as a metalloproteinase is a key enzyme in processing ECM. In this study we wanted to evaluate the role of BMP-1 on enhancing bone repair in ret femoral fracture model and a rabbit ulna critical size defect model. Materials and Methods : An osteotomy in the proximal third of the femur was made in male Sprague-Dawley rats (250-300 g) using a circular saw. The fragments were repositioned and fixed by an intramedullary Kirschner pin. The rats were randomly assigned to four groups: control group without any therapy, group receiving 3 μg of rhBMP-1 iv 3 times a week, group receiving 50 μg BMP-1-3 antibody iv once a week and the final group receiving 50 μg BMP-1-1 once a week. The effect of the treatment was monitored by radiographs every two weeks up to the 6th week when the animals were sacrificed and femurs were scanned by µCT (µCT 40, Scanco). Bone biomechanical testing was done using a Material testing system Model 810 (MTS Systems Corp). An critical size defect model was used to evaluate the efficacy of BMP1 in bone healing of adult male New Zealand White rabbits weighing around 3 kg. Ulnar critical size defect of 15mm was made using an battery powered bone saw (Aesculap). Autologus whole blood coagulum device (WBCD) was created by collecting 2 mL of full blood from the rabbit marginal ear vein in a tube without any anticoagulant. Operated animals were randomly assigned to four groups. Control group was implanted only with WBCD while BMP-1 group was implanted with WBCD containing 20µg of BMP-1. BMP-1-1 and BMP-1-3 antibody groups were implanted with 50µg of BMP1-1 and BMP-1-3 antibodies respectively. Bone repair process was monitored through the course of 8 weeks. Animals were scanned in vivo radiographically in two time points (4 and 8 weeks) and ex vivo by µCT (SkyScan 1076) on week 8. Results: Systemically applied BMP-1 enhanced bone repair in rat fracture model by increasing extracellular matrix processing and deposition at the fracture site. BMP-1 neutralizing antibodies delayed fracture repair by sequestering BMP-1 protease activity. Biomechanical testing confirmed results obtained by µCT analysis. In the rabbit critical size defect model whole blood coagulum device (WBCD) combined with BMP-1 resulted after 8 weeks with the almost full rebridgement of the defect. Inhibitory effect of BMP-1 antibodies limited the bone repair to osteotomy ends. Conclusions : Enhanced bone repair by BMP-1 in fracture model and in the critical size defect model proved its essential role in fracture repair while BMP-1 inhibition by specific BMP-1 isoforms resulted in delayed fracture repair due to prolonged ECM processing.

BMP1-3, fracture repair, bone healing

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