Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, 33 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea.
Hard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National University, 33 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea.
Tissue Eng Regen Med. 2021 Feb;18(1):155-164. doi: 10.1007/s13770-020-00290-4. Epub 2020 Oct 14.
The delivery of recombinant human bone morphogenetic protein 2 (rhBMP2) by using various carriers has been used to successfully induce bone formation in many animal models. However, the effect of multiple administration of rhBMP2 on bone formation and BMP2 antibody production has not been determined. Our aim was to examine the bone formation activity of rhBMP2 and serum levels of anti-BMP2 antibodies following the repeated administration of rhBMP2 in mice.
Absorbable collagen sponges or polyphosphazene hydrogels containing rhBMP2 were subcutaneously implanted or injected into one side on the back of six-week-old C57BL/6 mice. Three or 4 weeks later, the same amount of rhBMP2 was administered again with the same carrier into the subcutaneous regions on the other side of the back or into calvarial defects. The effects of a single administration of rhBMP2 on the osteoinductive ability in the ectopic model were compared with those of repeated administrations. In vivo ectopic or orthotopic bone formation was evaluated using microradiography and histological analyses. Serum concentrations of anti-rhBMP2 antibodies were measured by ELISAs.
Re-administration of the same amount of rhBMP2 into the subcutaneous area showed a comparable production of ectopic bone as after the first administration. The bone forming ability of repeated rhBMP2 administrations was equal to that of single rhBMP2 administration. The administration of rhBMP2 into calvarial defects, following the first subcutaneous administration of rhBMP2 on the back, completely recovered the defect area with newly regenerated bone within 3 weeks. Repeated administration of rhBMP2 at 4-week intervals did not significantly alter the serum levels of anti-BMP2 antibodies and did not induce any inflammatory response. The serum obtained from rhBMP2-exposed mice had no effect on the ability of rhBMP2 to induce osteogenic gene expressions in MC3T3-E1.
We suggest that the osteoinductive ability of rhBMP2 is not compromised by repeated administrations. Thus, rhBMP2 can be repeatedly used for bone regeneration at various sites within a short duration.
在许多动物模型中，使用各种载体递送重组人骨形态发生蛋白 2（rhBMP2）已成功诱导骨形成。然而，rhBMP2 的多次给药对骨形成和 BMP2 抗体产生的影响尚未确定。我们的目的是在小鼠中重复给予 rhBMP2 后，检查 rhBMP2 的骨形成活性和血清中抗-BMP2 抗体的水平。
将含有 rhBMP2 的可吸收胶原海绵或聚磷腈水凝胶皮下植入或注射到 6 周龄 C57BL/6 小鼠背部的一侧。3 或 4 周后，用相同的载体将相同量的 rhBMP2 再次给予背部另一侧的皮下区域或颅骨缺损处。比较 rhBMP2 单次给药与重复给药对异位模型成骨诱导能力的影响。通过微射线照相术和组织学分析评估体内异位或原位骨形成。通过 ELISA 测量血清中抗 rhBMP2 抗体的浓度。
将相同量的 rhBMP2 再次给予皮下区域显示出与第一次给药后相当的异位骨生成。重复给予 rhBMP2 的成骨能力与单次 rhBMP2 给药相当。在背部首次皮下给予 rhBMP2 后，将 rhBMP2 给予颅骨缺损处，在 3 周内完全恢复了缺陷区域，并生成了新的再生骨。每隔 4 周重复给予 rhBMP2 不会显著改变血清中抗-BMP2 抗体的水平，也不会引起任何炎症反应。从 rhBMP2 暴露的小鼠获得的血清对 rhBMP2 诱导 MC3T3-E1 成骨基因表达的能力没有影响。
我们认为 rhBMP2 的成骨能力不会因重复给药而受到影响。因此，rhBMP2 可以在短时间内在不同部位重复用于骨再生。
