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

双膦酸盐已被发现是焦磷酸盐的类似化合物。它们对结合骨有很强的亲和力，对骨吸收有很强的抑制作用。最近，它们对破骨细胞功能的作用已被阐明，但我们先前的研究表明，双膦酸类化合物的其他作用可能与其对骨组织的药理作用有关。我们致力于寻找药物的新靶点，并进行了本研究。体内研究表明，双膦酸类药物可抑制低钙喂养所致的大鼠骨密度下降。同时，敌敌畏显著刺激骨形成表面的矿物质沉积速率。在体外实验中，双膦酸盐可促进骨髓细胞培养中矿化结节的形成，这种作用可能与成骨细胞的分化进程有关。结果表明，双膦酸类化合物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，双膦酸能阻断Walker256/S乳腺癌细胞接种所致的大鼠骨吸收。由于荷瘤大鼠的骨吸收是由于抑制了黄体生成素-促性腺激素释放激素系统诱导的雌激素合成所致，双膦酸类药物目前对实验大鼠的抑制作用提示了该药物治疗这类疾病的有效性。从这些结果中，阐明了双膦酸类药物对破骨细胞和成骨细胞的新靶点，这些靶点对于了解该药物对骨组织的作用具有重要意义。

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.