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Functional analysis of apoptosis-related proteins in osteoclasts

破骨细胞凋亡相关蛋白的功能分析

基本信息

批准号：
18591652
负责人：
KADONO Yuho
金额：
$ 2.55万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591652/
关键词：
osteoclast apoptosis Bcl-2 family bone resorption Bc1-2ファミリー

项目摘要

Homeostasis of the skeletal system is maintained by a bone remodeling process, which is dependent on a delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts. Osteoclasts are multinucleated giant cells primarily responsible for bone resorption, which rapidly underwent apoptosis after finishing their tasks. We have previously reported that proapoptotic Bcl-2 family molecule Bim played an essential role for apoptosis of osteoclasts, and moreover played a pivotal role on bone resorption activity of osteoclasts. However, the roles of anti-apoptotic molecule Bcl-2, Bcl-xL on survival and bone resorption activity of osteoclasts have not been fully elucidated. We therefore regarded Bcl-2 family molecules as the organic molecular complex, and generated bcl-2-/-, bcl-2-/- bim+/- mice, and bcl-x conditional knockout mice and analyzed the roles of the molecules on survival and bone resorption activity of osteoclasts. We demonstrated that anti-apoptotic molecule Bcl-2 and Bcl-xL promoted the survival of osteoclasts in ex vivo experiments. Remarkably, Bcl-xL suppressed the bone resorption activity of osteoclasts ; in contrast, Bcl-2 reasonably promoted the function of osteoclasts in ex vivo and in vivo experiments though they are the same anti-apoptotic Bcl-2 subfamily. The in vivo analysis of the role of bcl-2 deficiency in the skeletal tissue is hampered by the ill health and early death of bcl-2-/-mice. We therefore generated bcl-2-/- bim+/-mice in which a single bim allele was knocked out and represented that they grew normally into adults. We revealed that Bcl-2 was essential for maintaining normal bone homeostasis in the adult mice by analyzing bcl-2-/- bim+/-mice. Thus, Bcl-2 family proteins play pivotal roles on the function of respective cells in addition to regulation of their life and death.

骨骼系统的稳态通过骨重建过程来维持，骨重建过程依赖于成骨细胞的骨形成和破骨细胞的骨吸收之间的微妙平衡。破骨细胞是一种多核巨细胞，主要负责骨吸收，完成任务后迅速凋亡。我们以前报道过促凋亡Bcl-2家族分子Bim在破骨细胞凋亡中起重要作用，而且在破骨细胞的骨吸收活性中起关键作用。然而，抗凋亡分子Bcl-2，Bcl-xL对破骨细胞的存活和骨吸收活性的作用尚未完全阐明。因此，我们将Bcl-2家族分子视为有机分子复合物，建立了bcl-2-/-、bcl-2-/- bim+/-和bcl-x条件性基因敲除小鼠模型，分析了这些分子对破骨细胞存活和骨吸收活性的影响。我们证明，抗凋亡分子Bcl-2和Bcl-xL促进破骨细胞在体外实验中的生存。值得注意的是，Bcl-xL抑制破骨细胞的骨吸收活性;相反，Bcl-2在体外和体内实验中合理地促进破骨细胞的功能，尽管它们是相同的抗凋亡Bcl-2亚家族。bcl-2缺陷在骨骼组织中的作用的体内分析受到bcl-2-/-小鼠的健康状况不佳和过早死亡的阻碍。因此，我们产生了bcl-2-/- bim+/-小鼠，其中单个bim等位基因被敲除，并表示它们正常生长为成年小鼠。我们通过分析bcl-2-/- bim+/-小鼠，揭示了Bcl-2对于维持成年小鼠的正常骨稳态是必不可少的。因此，Bcl-2家族蛋白除了调节细胞的生命和死亡外，还对相应细胞的功能起关键作用。