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Search for the new target points of bisphosphonates in bone cells: Their inhibitory actions on bone resorption and the stimulatory actions on bone formation

寻找双膦酸盐在骨细胞中的新靶点：其对骨吸收的抑制作用和对骨形成的刺激作用

基本信息

批准号：
13470391
负责人：
OHYA Keiichi
金额：
$ 8.77万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

Bisphosphonates have been found as an analogue compound of pyrophosphates. They have a strong affinity for binding bone and show a strong inhibitory action on bone resorption. Recently their actions for osteoclast function have been clarified, but our previous studies indicate that other actions of bisphosphonate might be related with the pharmacological effects on bone tis-sue. We focused to find the new targets of the drug and performed the present research. In vivo studies demonstrated that the decrease of bone mineral density induced by the low-calcium feeding in rats was inhibited by the treatments of bisphosphonate. At the same time, bisphos-phonate significantly stimulated the mineral apposition rate of bone formation surface. In in vitro study, the mineralized nodule formation was increased by bisphosphonate in bone marrow cell culture and this effect might be accompanied with the progress of osteoblast differentiation. The-se results indicated that the action of bisphosphonates on bone tissues is the combined effects of the inhibitory actions on bone resorption and the stimulatory actions on bone formation. In addition, bisphosphonate blocked the bone resorption induced by the inoculation of Walker256/s mammary carcinoma cells in rats. Because the bone resorption in this carcinoma bearing rats is due to the inhibition of the estrogen synthesis induced by the LH-RH system, the present inhibi-tory effects of bisphosphonate on the experimental rats indicated the usefulness of the drug for the treatment of this type of disease From these results, the new targets points of bisphospho-nates both on the osteoclasts and osteoblasts are clarified and these targets of bisphosphonates are important to understand the actions of the drug on bone tissues.

已发现双膦酸盐是焦磷酸盐的类似物化合物。它们具有很强的骨结合亲和力，对骨吸收有很强的抑制作用。近年来，双膦酸盐对破骨细胞的作用已被阐明，但我们的研究表明，双膦酸盐的其他作用可能与其对骨组织的药理作用有关。本研究的目的是寻找新的药物作用靶点，并开展本课题的研究。体内研究表明，双膦酸盐可抑制低钙喂养引起的大鼠骨密度降低。同时，双酚A能显著促进骨形成表面的矿物沉积速率。体外研究表明，双磷酸盐可以增加骨髓细胞培养中矿化结节的形成，这种作用可能伴随着成骨细胞分化的进程。结果表明，双膦酸盐对骨组织的作用是抑制骨吸收和促进骨形成的综合作用。此外，双膦酸盐阻断接种Walker 256/s乳腺癌细胞诱导的大鼠骨吸收。由于荷瘤大鼠的骨吸收是由于LH-RH系统抑制雌激素合成所致，因此，双膦酸盐对实验大鼠的抑制作用表明，该药物对治疗这类疾病是有效的。新的目标点双磷酸，破骨细胞和成骨细胞上的靶点被阐明，并且双膦酸盐的这些靶点对于理解药物对骨组织的作用是重要的。