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Effects of Low Molecular Weight Compounds on Osteoclastic Bone Resorption in vivo and in vitro.

低分子量化合物对体内和体外破骨细胞骨吸收的影响。

基本信息

批准号：
15380077
负责人：
NAGAI Kazuo
金额：
$ 9.79万
依托单位：
Chubu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

In the course of screening for natural compounds that prevent or cure osteoporosis, we found reveromycin A (RMA), mevastatin, destruxins, which are targeted to the function and survival of mature osteoclats. In the present study, we determined the effects of these three compounds on osteoclastic bone resorption in vitro and in vivo. The effect of RM-A was decreased by disruption of the acidic microenvironment in activated osteoclasts, and increased in acidic culture condition. RMA also inhibited the increase of bone resorption in ovariectomised mice. These results indicate that RMA could be a good candidate for a new anti-resorptive medicine with high specificity against activated osteoclasts. Mevastatin was shown to inhibit early differentiation of osteoclasts from their progenitor cells such as RAW 264 cells or M-CSF-dependent bone marrow cells in the presence of RANKL. The inhibitory effects of mevastatin were overcome by the addition of mevalonate, farnesyl pyrophosphate or geranylgeranyl pyrophosphate. Geranylgeranyl transferase inhibitor, but not farnesyl transferase inhibitor, inhibited early differentiation of osteoclasts induced by RANKL, suggesting that the geranylgeranylation of these proteins is involved in the inhibitory effect of mevastatin on early differentiation of osteoclasts. Cyclodepsipeptides, destruxin B and E, were found to inhibit osteoclastic bone resorption without affecting osteoclast differentiation and survival, but destruxin E did not inhibit the increase of bone resorption in ovariectomised mice.

在筛选预防或治疗骨质疏松症的天然化合物的过程中，我们发现了回复霉素A（RMA），美伐他汀，destruxins，它们针对成熟骨细胞的功能和存活。在本研究中，我们确定了这三种化合物对骨细胞骨吸收的影响，在体外和体内。破骨细胞酸性微环境的破坏使RM-A的作用减弱，酸性培养条件下RM-A的作用增强。RMA还抑制卵巢切除小鼠骨吸收的增加。这些结果表明，RMA可能是一个很好的候选人，一个新的抗骨吸收药物具有高度特异性对活化破骨细胞。在RANKL存在下，美伐他汀显示出抑制破骨细胞从其祖细胞（如RAW 264细胞或M-CSF依赖性骨髓细胞）的早期分化。通过加入甲羟戊酸、焦磷酸法呢酯或焦磷酸香叶基香叶基酯克服了美伐他汀的抑制作用。香叶基香叶基转移酶抑制剂，而不是法尼基转移酶抑制剂，抑制破骨细胞的早期分化RANKL诱导，这表明这些蛋白的香叶基香叶基化参与了美伐他汀对破骨细胞的早期分化的抑制作用。发现环缩肽类，destruxin B和E，抑制破骨细胞的骨吸收，而不影响破骨细胞的分化和存活，但destruxin E不抑制卵巢切除小鼠骨吸收的增加。