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

在筛选预防或治疗骨质疏松症的天然化合物的过程中，我们发现了以成熟骨细胞的功能和存活为目标的reveromycin A (RMA), mevastatin, destruxins。在本研究中，我们在体外和体内测定了这三种化合物对破骨细胞骨吸收的影响。破坏活化破骨细胞的酸性微环境会降低RM-A的作用，而在酸性培养条件下作用增强。RMA还能抑制去卵巢小鼠骨吸收的增加。这些结果表明，RMA可能是一种新的抗骨吸收药物，对活化的破骨细胞具有高特异性。研究显示，在RANKL存在的情况下，美伐他汀可以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。通过添加甲戊酸盐、焦磷酸法尼酯或焦磷酸香叶基香叶基来克服美伐他汀的抑制作用。Geranylgeranyl转移酶抑制剂抑制RANKL诱导的破骨细胞早期分化，而不是farnesyl转移酶抑制剂，提示这些蛋白的geranylgeranyation参与了美伐他汀对破骨细胞早期分化的抑制作用。环沉积肽破骨蛋白B和E抑制破骨细胞骨吸收，但不影响破骨细胞分化和存活，但破骨蛋白E不抑制去卵巢小鼠骨吸收的增加。

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.