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Background: Native BMP extracts from reindeer effectively induce ectopic new bone formation in vivo, but their bone healing properties have not yet been evaluated. We investigated the effect of reindeer BMP extracts on the healing of long bone defects., Methods: The implants tested contained 5 mg or 10 mg of unsterilized BMP extract from reindeer and 10 mg of gamma-sterilized BMP extract administered with collagen carrier (Lyostypt, B. Braun, Germany). 70 micro g of rhBMP-2 with collagen carrier (InductOs; Wyeth Europa) served as positive control, and collagen implants (Lyostypt) and untreated defects served as negative controls. New Zealand White rabbits with 1.5 cm of critical-size radius bone defects were used, with 8 weeks of follow-up., Results: Radiographic analysis showed bone formation (BF) to be higher in all groups containing BMPs than in the untreated controls. BF was also higher in the rhBMP-2 group, and marginally higher in the group treated with 10 mg of unsterilized reindeer BMP extract (p = 0.06) as compared to the collagen controls. Bone union (BU) was better in the unsterilized BMP extract groups and rhBMP-2 group than in the untreated controls. BU was also better in the implants with 10 mg of unsterilized reindeer BMP extract and rhBMP-2 than in the collagen-treated implants. The mean area of new bone at the site of the defect proved to be higher in all implants containing BMP than in the untreated defects. It was also higher in the groups with 10 mg of unsterilized reindeer BMP extract and rhBMP-2 than in the collagen-treated controls. Mechanical tests showed torsional stiffness of the bones to be higher in the group with 10 mg of unsterilized BMP extract than in the collagen group. The mean cross-sectional bone area measured by pQCT densitometry was higher in the rhBMP-2 group than in the collagen group. The mean bone density at the defect area was higher in the group with 10 mg of unsterilized BMP than in the rhBMP-2 group., Interpretation: We conclude that both reindeer BMP extract and rhBMP-2 induced improved healing of the rabbit radius bone defects at the doses used. Gamma sterilization of reindeer BMP extract reduced osteoinductivity slightly, but not significantly.

Bone morphogenetic proteins (BMPs) are members of the TGF-beta superfamily. They are capable of inducing ectopic bone formation. Until now, the main interest has been focused on mammalian osteoinductive BMPs, and there are no reports of native BMP extracts of birds. In this study, we isolated and characterized native BMPs of ostrich (Struthio camelus) and compared them with identically isolated native bovine (cow) and reindeer BMPs with regard to BMP pattern and osteoinductive capacity. The ostrich BMP pattern differed markedly from that of cow and reindeer BMP in non-reduced SDS-PAGE, reduced SDS-PAGE and Western blot. The differences in isoelectric focusing analysis were smaller. However, the ostrich BMP extract had a peak at pH 5.1, clearly differing from the BMPs of cow and reindeer. The osteoinductive capacity and density of ectopic bone, induced by BMP extracts in a mouse thigh muscle pouch, were determined radiographically. The ostrich BMP extract displayed significantly lower osteoinductive capacity and density of induced bone than the bovine and reindeer BMP extracts. In conclusion, our results indicate that the BMP pattern of birds differs considerably from that of mammals, and that the osteoinductive capacity of BMPs and the density of induced bone are lower in birds than in mammals. They also suggest that the bone metabolism of birds is adapted to make light bones suitable for flying.

Background: Bone morphogenetic proteins (BMPs), which are capable of stimulating the production of new bone, must be sterilized before preclinical and clinical use to reduce the risk of infections and associated complications. In this study, we investigated the effects of gamma sterilization on the osteoinductivity of native reindeer BMP extract in the Balb/C mouse thigh muscle pouch model., Methods: 5 mg of native reindeer BMP extract and 5 mg of bovine serum albumin were administered separately either in gelatine capsules or mixed with gelatine as injections. The dose of gamma irradiation was 4.1 Mrad. Unsterile capsules and injections served as controls. New bone formation was evaluated based on the incorporation of Ca45 and also radiographically 3 weeks after implantation., Results: Albumin-containing implants and injections did not induce new bone formation, as monitored in radiographs. Gamma sterilization did not reduce the osteoinductivity of native BMP extract in capsules, but a significant decrease in osteoinductivity--measured as area (50%) and Ca45 incorporation of new bone (27%)--was seen after injection. Gamma sterilization had no effect on the optical density of new bone induced by native BMP extract administered in capsules or by injection., Interpretation: We conclude that, as gamma irradiation did not reduce the osteoinductivity of reindeer BMP extract in gelatine capsules, this method appears to be suitable for sterilization of BMPs to be given in capsule form. Native reindeer BMP extract was more sensitive to irradiation in soluble collagen (gelatine) than BMP in gelatine capsules. This finding must be given serious consideration regarding treatment of patients, but the remaining activity may be sufficient for the induction of bone formation in preclinical and clinical situations.

Introduction: Bone morphogenetic proteins (BMPs) require carrier material for slow release and framing material for osteoconduction., Materials and Methods: The effect of a frame on early bone formation induced by partially purified native reindeer BMP in composite implants containing 3 mg of BMP, type IV collagen and tricalcium phosphate (TCP/Col/BMP) or hydroxyapatite (HA/Col/BMP) or biphasic tricalcium phosphate-hydroxyapatite (TCP/HA/Col/BMP) or biocoral (NC/Col/BMP) was evaluated using a mouse hind leg muscle pouch model. Collagen with native reindeer BMP (Col/BMP) and corresponding implants without native reindeer BMP served as controls. Evaluation was done by incorporation of 45Ca, radiographically and histologically 3 weeks after the implantation., Results: None of the implants without native reindeer BMP were able to induce new bone visible on radiographs. The area of new bone formation in the Col/BMP (p=0.026) and TCP/HA/Col/BMP (p=0.012) groups was significantly greater than in the TCP/Col/BMP group. The optical density of the new bone area was significantly greater in the TCP/HA/Col/BMP group than in the TCP/Col/BMP (p=0.036) or Col/BMP (p=0.02) groups. 45Ca incorporation was many times greater in all the groups containing native reindeer BMP than in the corresponding groups without BMP. In the Col/BMP (p=0.046) and TCP/HA/Col/BMP (p=0.046) groups, 45Ca incorporation was significantly greater than in the TCP/Col/BMP group. No significant differences were found in any parameters between HA/Col/BMP and NC/Col/BMP groups and the other BMP-containing groups., Conclusions: Hydroxyapatite, biocoral and biphasic tricalciumphosphate-hydroxyapatite are equally good as framing material for native reindeer BMP, while tricalciumphosphate is somewhat worse. Osteoinduction of native reindeer BMP works well with collagen alone.

We studied the effects of ethylene oxide sterilization (Steri-Vac 4XL, temperature 29 degrees C, exposure time 4 h 10 min, ethylene oxide concentration 860 mg/l) on the osteoinductivity of partially purified native reindeer bone morphogenetic protein (BMP) in a hind leg muscle pouch model of male NMRI mice. BMP was administered in implants containing 3 mg in a collagen carrier. Implants without sterilization and without BMP served as controls. New bone formation was evaluated based on the calcium yield, radiographic and histological examination 3 weeks after implantation. The implants without BMP were not able to induce new bone visible in radiographs. In the sterilized BMP group, the mean area of new bone was 35% ( p=0.004) and density 32% ( p=0.000) smaller than in the nonsterilized group. Calcium yield was 20% lower in the sterilized group than in the nonsterilized group, but this difference was not significant ( p=0.22). It was many times lower in the group without BMP than in the above-mentioned groups ( p=0,001). We conclude that ethylene oxide gas sterilization reduces the bone-forming activity of native reindeer BMP by one third.

Background and Aims: Bone morphogenetic proteins (BMPs) are usually administered with a solid framing material during open surgery. In some instances, percutaneous administration of injectable BMP would be preferable. We tested the new bone-forming activity of injectable native reindeer BMP extract in the Balb/C mouse thigh muscle pouch model., Materials and Methods: The injectable implants contained 6 mg of native reindeer BMP extract and either physiological saline (NaCl/BMP) or collagen (Gel/BMP). Corresponding implants without BMP served as controls. New bone formation was evaluated based on incorporation of Ca45 and radiographically three weeks after the injection into the mouse thigh muscles., Results: None of the injections without BMP were able to induce new bone visible in radiographs, whereas the injections with BMP induced new bone effectively. There were no significant differences in the area of new bone (p = 0.247) and its density (p = 0.739) between the NaCl/BMP and Gel/BMP groups. Ca-45 incorporation was multifold in the NaCl/BMP and Gel/BMP groups compared to the controls (p = 0.000). No significant differences in Ca-45 incorporation (p = 0.739) between the NaCl/BMP and Gel/BMP groups were observed., Conclusion: Our results suggest that BMP can be administered percutaneously, and that collagen and physiological saline are equally good carriers of injectable implants of native reindeer BMP.