Low Molecular Weight Compounds That Regulate Bone Metabolism

调节骨代谢的低分子量化合物

• 批准号: 13460036
• 负责人: NAGAI Kazuo
• 金额: $ 5.89万
• 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: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13460036/
• 关键词: destruxins; reveromycin A; EGCG; bone resorption; osteoclast; osteoporosis; cell death; calcium; 骨芽細胞; 骨形成; 分化; メバスタチン; ゲラニルゲラニル化; 生存; アポトーシス; 活性化

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

在筛选食物中的天然化合物和微生物代谢产物预防或治疗骨质疏松症的过程中，我们发现了destruxins，reveromycin A（RMA）和（-）-表没食子儿茶素-3-没食子酸酯（EGCG）。发现环缩酚肽，破坏素B和E，抑制骨细胞的骨吸收，而不影响破骨细胞的分化和存活。破坏素以剂量依赖性方式可逆地诱导功能性破骨细胞的形态学变化。电子显微镜分析显示，destruxin处理过的破骨细胞在牙本质切片上没有明显的透明区或皱褶边界。这些结果表明，抗骨吸收作用的结果是由于破坏破骨细胞的形态结构。发现RMA通过诱导成熟破骨细胞凋亡来抑制骨吸收。RMA的作用伴随着细胞色素c从线粒体释放到细胞质中，半胱天冬酶激活和破骨细胞核碎裂。RMA ...更多信息 诱导具有肌动蛋白环和吸收能力的活化破骨细胞凋亡。RMA对活化破骨细胞的作用可被V-ATP酶特异性抑制剂康卡霉素B或碳酸酐酶抑制剂乙酰唑胺阻断，后者可阻止破骨细胞膜周围的酸化。RMA还能抑制PTH引起的TPTX大鼠血清钙浓度升高。这些结果表明，RMA对活化的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可能是一个很好的候选人，一个新的抗吸收骨质疏松症的药物具有高度特异性对活化破骨细胞。表没食子儿茶素没食子酸酯通过芬顿反应促进氧化应激特异性诱导骨吸收破骨细胞的细胞死亡。表没食子儿茶素没食子酸酯能特异性诱导破骨细胞凋亡，表明表没食子酸没食子酸酯具有预防或治疗骨质疏松症的潜力。少

项目成果

K.Suda, J.-T.Woo, M.Takami, P M Sexton, K.Nagai: "Lipopolysaccharide supports survival and fusion of preosteoclasts independent of TNF-α, IL-1 and RANKL"J. Cell Physiol.. 190. 101-108 (2002)

K.Suda、J.-T.Woo、M.Takami、PM Sexton、K.Nagai：“脂多糖支持前破骨细胞的存活和融合，不依赖于 TNF-α、IL-1 和 RANKL”J. 190。 101-108（2002）

J. Ding, J.T Woo and K. Nagai: "The effects of retinoic acid on reversing the adipocyte differentiation into an osteoblastic tendency"Cytotechnology. 36. 125-136 (2001)

J. Ding、J.T Woo 和 K. Nagai：“视黄酸对逆转脂肪细胞分化为成骨细胞倾向的影响”细胞技术。

H.Nakagawa, M.Wachi, J.T.Woo, M.Kato, L.S.Lee, K.Nagai: "Fenton reaction is primarily involved in a mechanism of (-)-epigallocatechin-3-gallateto induce osteoclastic cell death"Biochem. Biophys Res Commun. 292. 94-101 (2002)

H.Nakakawa、M.Wachi、J.T.Woo、M.Kato、L.S.Lee、K.Nagai：“芬顿反应主要涉及 (-)-表没食子儿茶素-3-没食子酸酯诱导破骨细胞死亡的机制”Biochem。

H.Nakagawa, M.Wachi, J.T.Woo, M.Kato, I.S.Lee, K.Nagai: "Fenton reaction is primarily involved in a mechanism of (-)-epigallocatechin-3-gallate to induce osteoclastic cell death"Biochem. Biophys. Res. Commun.. 292. 94-101 (2002)

H.Nakakawa、M.Wachi、J.T.Woo、M.Kato、I.S.Lee、K.Nagai：“芬顿反应主要涉及 (-)-表没食子儿茶素-3-没食子酸酯诱导破骨细胞死亡的机制”Biochem。

K. Igarashi, J.T. Woo and P H Stern: "The effects of a selective cyclooxygenase-2 inhibitor, celecoxib, on bone resorption and osteoclastogenesis in vitro"Biochemical Pharmacology. 63. 523-532 (2002)

K.五十岚，J.T.