Prevention of fracture healing in rats by an inhibitor of angiogenesis
Prevention of fracture healing in rats by an inhibitor of angiogenesis
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DOI：
10.1016/s8756-3282(01)00608-1
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发表时间：
2001-12-01
期刊：
影响因子：
4.1
通讯作者：
Majeska, RJ
中科院分区：
文献类型：
--
作者：
Hausman, MR;Schaffler, MB;Majeska, RJ
血管生成被认为对骨折愈合至关重要，但其在愈合过程中的作用仍知之甚少。血管生成抑制剂通过特异性靶向血管细胞来阻止新血管形成，目前正在开发用于癌症化疗，并且可能是确定血管生成损伤对骨折愈合影响的强大工具。在本研究中，我们在已建立的大鼠模型系统中直接测试了血管生成抑制剂 TNP-470 对闭合性股骨骨折愈合的影响。从骨折后第一天开始，动物接受治疗有效抗肿瘤剂量的血管生成抑制剂，或体重调整量的载体。在 21 天的时间内，每周通过放射线照相和组织学评估骨折愈合的进展，在第 24 天通过生物力学测试进行功能评估。根据所有三个标准，血管生成抑制剂治疗完全阻止了骨折愈合。愈伤组织和骨膜编织骨的形成均受到抑制，表明成骨的膜内和软骨内途径均受到影响。由此产生的组织类似于临床上骨折愈合失败病例中常见的“萎缩性诺曼尼翁”，但在动物模型中很少实现。这些结果表明，血管生成对于骨折愈合的早期阶段至关重要，并表明该模型系统可能有助于理解由于血管损伤导致的骨折不愈合的机制。最后，数据提出了骨折愈合受损可能是抗血管生成药物临床治疗的副作用的可能性。 (C) 2001 年，Elsevier Science Inc. 保留所有权利。
Angiogenesis is considered essential to fracture healing, but its role in the healing process remains poorly understood. Angiogenesis inhibitors, which block new blood vessel formation by specifically targeting vascular cells, are currently under development for use in cancer chemotherapy, and are potentially powerful tools for defining the consequences of angiogenic impairment on fracture healing. In this study, we directly tested the effects of the angiogenesis inhibitor TNP-470 on the healing of closed femoral fractures in an established rat model system. Beginning I day after fracture, animals received either angiogenesis inhibitor at a therapeutically effective antitumor dose, or a weight-adjusted amount of carrier vehicle. The progress of fracture healing was assessed at weekly intervals for 21 days by radiography and histology, functional assessment was carried out at day 24 by biomechanical testing. By all three criteria, treatment with the angiogenesis inhibitor completely prevented fracture healing. Formation of both callus and periosteal woven bone were suppressed, indicating that both the intramembranous and endochondral pathways of osteogenesis were affected. The resulting tissue resembled "atrophic nomanions" often seen clinically in cases of failed fracture healing, but rarelly achieved in animal models. These results show that angiogenesis is essential to very early stages of fracture healing, and suggest this model system may be useful for understanding the mechanisms underlying fracture nonunions due to vascular impairment. Finally, the data raise the possibility that impairment of fracture healing may be an adverse effect of clinical treatments with antiangiogenic drugs. (C) 2001 by Elsevier Science Inc. All rights reserved.