权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Microbial metabolites that regulate osteoclast differentiation and function

调节破骨细胞分化和功能的微生物代谢产物

基本信息

批准号：
11660078
负责人：
NAGAI Kazuo
金额：
$ 2.37万
依托单位：
Tokyo Institute of Technology (TIT)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11660078/
关键词：
osteoclast bone resorption compactin destruxins reveromycin A actin ring apoptosis cell fusion reveromycin A destruxin E apoptosis actin ring 抑制剤

项目摘要

To obtain new insights into the mechanisms of differentiation and function of osteoclasts and to develop natural compounds as anti-resortive medicines for clinical application, we have screened microbial metabolites for low molecular weight compounds that inhibit the differentiation and function of osteoclasts. In the process of this screening we found compactin, destruxins and reveromycin A.Compactin inhibited the fusion process of prefusion osteoclasts into multinucleated osteoclasts, disrupted the actin ring of osteoclasts and inhibited bone resorption. The effects of compactin were suppressed by the addition of mevalonic acid lactone or its downastream products including farnesylpyrophosphate and gerahylgeranyl-pyrophosphate, but not by squalene. The results indicate that these effects of compactin are the consequence of the inhibition of prenylation of proteins that play an important role in the fusion process of preosteoclasts and in maintaining the actin ring integrity in osteoclasts. Destruxins, which are cyclomonodepsipeptides isolated from the antomogenous fungi, reversibly inhibited bone resorption through disrupting morphological structures including the actin ring in activated osteoclasts and inhibiting the polarization of osteoclasts on the bone without affecting viability of osteoclasts. They also affected the localization of c-src and a3 subunit of V-ATPase that are essential molecules osteoclasts. These results suggest that destruxins regulate polarization of osteoclasts. Reveromycin A induced apoptosis specifically in mature activated osteoclasts through release of mitochodrial cytochrome c into cytosol, and inhibited bone resorption. The specific effect of reveromycin A on activated osteoclasts was related to the acidic condition around membrane of activated osteoclasts.

为了获得破骨细胞分化和功能机制的新见解，并开发天然化合物作为临床应用的抗吸收药物，我们筛选了微生物代谢产物中抑制破骨细胞分化和功能的低分子量化合物。在这个筛选过程中，我们发现compactin，destruxins和reveromycin A.Compactin抑制融合前破骨细胞融合成多核破骨细胞，破坏破骨细胞的肌动蛋白环，抑制骨吸收。甲羟戊酸内酯或其下游产物法尼基焦磷酸和香叶基香叶基焦磷酸可抑制甲羟戊酸内酯的作用，但角鲨烯不抑制甲羟戊酸内酯的作用。结果表明，这些影响的compactin的异戊二烯化的蛋白质，在破骨细胞前体的融合过程中发挥重要作用，并在维持肌动蛋白环的完整性破骨细胞的抑制的后果。破坏素是从内生真菌中分离的环单缩酚肽，通过破坏包括活化的破骨细胞中的肌动蛋白环在内的形态结构和抑制破骨细胞在骨上的极化而不影响破骨细胞的活力，可逆地抑制骨吸收。它们还影响破骨细胞所必需的c-src和V-ATP酶α 3亚基的定位。这些结果表明，destruxins调节破骨细胞的极化。逆转霉素A通过释放线粒体细胞色素c到胞浆中，特异性地诱导成熟活化的破骨细胞凋亡，并抑制骨吸收。回复霉素A对活化破骨细胞的特异性作用与活化破骨细胞膜周围的酸性条件有关。