The local administration of TNF-α and RANKL antagonist peptide promotes BMP-2-induced bone formation
The local administration of TNF-α and RANKL antagonist peptide promotes BMP-2-induced bone formation
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DOI：
10.1016/j.job.2012.12.005
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发表时间：
2013-02-01
影响因子：
2.4
通讯作者：
Aoki, Kazuhiro
中科院分区：
文献类型：
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作者：
Khan, Abdulla Al Masud;Alles, Neil;Aoki, Kazuhiro
目的：由于高剂量的骨形态发生蛋白(BMPs)需要在灵长类动物体内实现一定程度的骨再生，从而导致炎症等副作用，因此使用BMPs和可以减少BMPs需求量的药物的联合治疗已经被开发出来。最近，我们发现皮下注射W9肽(W9)，促进BMP诱导的异位骨形成。W9是一种肿瘤坏死因子-α和核因子-kB受体激活剂配体拮抗剂。由于已知的肿瘤坏死因子-α可以减少骨形成，我们利用缺乏肿瘤坏死因子-α、肿瘤坏死因子1型受体(TNFR1)缺陷和野生型(WT)的小鼠研究了W9促进骨形成的机制。方法：将含BMP-2(1 MU G)或BMP-2(1 MU G)加W9(0.56 mg)(BMP-2+W9)的胶原片植入5周龄雄性小鼠背部肌肉。于植入后第12天处死动物。对解剖的异位骨进行放射学和组织形态计量学分析。结果：与BMP-2组相比，BMP-2+W9组小鼠异位骨明显增多。骨组织形态计量学显示，与BMP-2组相比，BMP-2+W9组小鼠的成骨细胞表面指数和矿化骨指数显著增加。有趣的是，W9还增加了BMP-2诱导的异位骨中的骨矿物质含量，无论是在肿瘤坏死因子-a缺乏的小鼠还是在TNFR1缺乏的小鼠中，其程度与WT小鼠相同。结论：W9促进骨形成的机制不是通过拮抗肿瘤坏死因子-α的作用。(C)2012年日本口腔生物学协会。爱思唯尔出版，版权所有。
Objectives: Because high doses of bone morphogenetic proteins (BMPs) are required to achieve a certain level of bone regeneration in primates, thereby causing side effects such as inflammation, combination therapies using BMPs along with agents that can reduce the required amount of BMPs have been developed. Recently, we found that subcutaneous injections of W9 peptide (W9), which has been established as a tumor necrosis factor (TNF)-a and receptor activator of nuclear factor-kB ligand (RANKL) antagonist, promoted BMP-induced ectopic bone formation. Since TNF-a is known to reduce bone formation, we investigated the stimulatory mechanism of W9 on bone formation by using TNF-a-deficient, TNF type 1 receptor (TNFR1)-deficient, and wild-type (WT) mice. Methods: Collagen discs containing either BMP-2 (1 mu g) alone or BMP-2 (1 mu g) with W9 (0.56 mg) (BMP-2+W9) were implanted into the back muscles of 5-week-old male mice. The animals were sacrificed on day 12 after implantation. Radiographic and histomorphometric analyses were performed on the dissected ectopic bones. Results: A significant increase in ectopic bone was observed in the BMP-2+W9 group compared to the BMP-2 group in WT mice. Bone histomorphometric technique revealed a significant increase of osteoblast surface and mineralized bone indices in the BMP-2+W9 group compared to the BMP-2 group in WT mice. Interestingly, W9 also increased the bone mineral content of ectopic bone induced by BMP-2 in both TNF-a deficient and TNFR1-deficient mice, to the same extent as in WT mice. Conclusion: Our data suggest that W9 promotes bone formation by a mechanism other than antagonism of TNF-a action. (C) 2012 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.