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Mechanisms of fracture healing in aged mice, which is dependent on COX-2 derived PGE_2

老年小鼠骨折愈合机制，依赖于 COX-2 衍生的 PGE_2

基本信息

批准号：
16592027
负责人：
TAKAGAKI Yuko
金额：
$ 1.92万
依托单位：
Kanagawa Dental College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16592027/
关键词：
fracture healing COX-2 low-intensity pulsed ultrasound endochondral)bone formation NSAIDs aging FGF-2 VEGF

项目摘要

Abstract : COX-2-induced PGE2, which can be provided by mechanical stimulation, crucially affects endochondral remodeling phase in fracture repair of aged mice. It not only orchestrates downstream molecules such as VEGFa and matrix metalloproteinases, but also controls FGF-2. Introduction : Fracture healing slows with age. In order to characterize the role of COX-2 in the delayed repair process in aged COX-2 knockout mice, we applied low-intensity pulsed ultrasound (LIPUS), which, we previously reported, induces COX-2 and is clinically used to accelerate repair processes. Methods : In one-yr-old COX-2 KO mice and their wild type littermates, micro focused X-ray computed tomography, (immuno) histochemical and mRNA analyses were conducted to characterize delay in healing of closed stabilized femur fracture. By administering combined EP2 and EP4 agonists from day 4 post fracture, rescue from the defect of both control and the LIPUS treated callus was confirmed to the level of wild type counterparts. Results : Cartilage formed relatively normally up to day 10. Thereafter, the repair process slowed down and was not accelerated by LIPUS. The treatment, however, effectively increased the rate of endochondral remodeling in the wild type littermates, a process prolonged in senescence. In the knockout callus, transcripts of such critical components as VEGFa and MMP-9 were entirely missing at day 7, regardless of exposure to LIPUS. In addition, the basal FGF-2 level was significantly elevated in the knockouts without further elevation by LIPUS. Conclusion : COX-2 is indispensable for fracture healing in aged mice ; if absent, endochondral remodeling is halted and the fracture gap filled with mesenchymal tissue persists. In addition to the loss of downstream VEGFa and matrix metalloproteinases, increased FGF-2 is likely to further delay the remodeling process.

摘要cox -2诱导的PGE2可通过机械刺激提供，对老年小鼠骨折修复过程中软骨内重构阶段有重要影响。它不仅协调下游分子如VEGFa和基质金属蛋白酶，而且还控制FGF-2。简介：骨折愈合随着年龄的增长而减慢。为了表征COX-2在老年COX-2基因敲除小鼠延迟修复过程中的作用，我们使用了低强度脉冲超声（LIPUS），我们之前报道过，LIPUS诱导COX-2，并在临床上用于加速修复过程。方法：对1岁COX-2 KO小鼠及其野生型窝仔进行微聚焦x线计算机断层扫描、（免疫）组织化学和mRNA分析，以表征闭合性稳定股骨骨折愈合延迟。从骨折后第4天开始联合使用EP2和EP4激动剂，对照组和LIPUS处理的愈伤组织的缺陷恢复到野生型的水平。结果：到第10天软骨形成相对正常。此后，修复过程减慢，LIPUS不加速。然而，治疗有效地增加了野生型窝鼠的软骨内重塑率，这一过程在衰老中延长。在基因敲除的愈伤组织中，VEGFa和MMP-9等关键成分的转录本在第7天完全缺失，无论是否暴露于LIPUS。此外，在基因敲除组中，基础FGF-2水平显著升高，而LIPUS没有进一步升高。结论：COX-2对老年小鼠骨折愈合有重要作用；如果缺失，软骨内重塑停止，骨折间隙继续充满间充质组织。除了下游VEGFa和基质金属蛋白酶的缺失外，FGF-2的增加可能会进一步延缓重塑过程。