Low Molecular Weight Compounds That Regulate Bone Metabolism

在筛选食品和微生物代谢产物中预防或治疗骨质疏松症的天然化合物的过程中，我们发现了破struxins， reveromycin A （RMA）和(-)-表没食子儿茶素-3-没食子酸酯（EGCG）。环沉积肽，破骨蛋白B和E抑制破骨细胞骨吸收，但不影响破骨细胞的分化和存活。破骨毒素以剂量依赖的方式可逆地诱导功能性破骨细胞的形态变化。电镜分析显示，破骨细胞在牙本质切片上没有明显的清晰区或褶皱边界。这些结果表明，抗骨吸收作用是由破骨毒素诱导极化破骨细胞形态结构紊乱引起的。RMA通过诱导成熟破骨细胞凋亡抑制骨吸收。RMA的作用伴随着细胞色素c从线粒体释放到细胞质，caspase激活和破骨细胞的核断裂。RMA更能诱导具有肌动蛋白环和再吸收能力的活化破骨细胞凋亡。RMA对活化破骨细胞的作用被康那霉素B（一种特异性v - atp酶抑制剂）或乙酰唑胺（一种碳酸酐酶抑制剂）阻断，后者可阻止破骨细胞膜周围酸化。RMA还能抑制PTH注射引起的TPTX大鼠血钙浓度升高。这些结果表明，RMA对活化破骨细胞的特异性作用是由于破骨细胞膜周围的酸性条件增加了RMA的细胞通透性。因此，RMA可能是一种新的抗骨质疏松药物，对活化的破骨细胞具有高特异性。EGCG通过Fenton反应促进氧化应激，特异性诱导骨吸收破骨细胞死亡。EGCG对破骨细胞凋亡的特异性诱导表明EGCG可能是预防或治疗骨质疏松症的药物。少

In the course of screening for the natural compounds in foods and microbial metabolites that prevent or cure osteoporosis, we found destruxins, reveromycin A (RMA) and (-)-Epigallocatechin-3-gallate (EGCG). Cyclodepsipeptides, destruxin B and E, were found to inhibit osteoclastic bone resorption without affecting osteoclast differentiation and survival. Destruxins reversibly induced morphological changes in functional osteoclasts in a dose-dependent manner. Electron microscopical analysis revealed that destruxin-treated osteoclasts on dentine slices have no prominent clear zones or ruffled borders. These results indicate that the anti-resorptive effects result from disorder of morphological structures in polarized osteoclasts induced by destruxins. RMA was found to inhibit bone resorption by inducing apoptosis in mature osteoclasts. The effect of RMA is accompanied by cytochrome c release from mitochondria into cytoplasm, caspase activation and nuclear fragmentation in osteoclasts. RMA … More induced apoptosis in activated osteoclasts having actin ring and resorption capability. The effect of RMA on activated osteoclasts was blocked by concanamycin B, a specific V-ATPase inhibitor or by acetazolamide, a carbonic anhydrase inhibitor, which prevents the acidification around the membrane of osteoclasts. RMA also inhibited the increase of serum calcium concentration induced by PTH injection in TPTX Rat. These results indicate that specific effect of RMA on activated osteoclasts results from acidic condition around the membrane of osteoclasts that increase cell permeability of RMA. Thus, RMA could be a good candidate for a new anti-resorptive osteoporotic medicine with high specificity against activated osteoclasts. EGCG specifically induced cell death in bone resorbing osteoclasts by promoting oxidative stress via Fenton reaction. Specific induction of apoptosis in osteoclasts by EGCG indicated the potentiality of EGCG as a prophylactic or therapeutic agent against osteoporosis. Less