madindoline A（一种新型的gp130非肽拮抗剂）抑制骨吸收。,Proceedings of the National Academy of Sciences of the United States of America

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madindoline A（一种新型的gp130非肽拮抗剂）抑制骨吸收。
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2002 Nov 12 , DOI: 10.1073/pnas.232562799
Masahiko Hayashi ₁ , Mun-Chual Rho ₁ , Akiko Enomoto ₁ , Akiko Fukami ₁ , Yong-Pil Kim ₁ , Yuji Kikuchi ₁ , Toshiaki Sunazuka ₁ , Tomoyasu Hirose ₁ , Kanki Komiyama ₁ , Satoshi Omura ₁

Affiliation

IL-6是一种多功能细胞因子，参与调节某些类型肿瘤细胞的分化，抗体产生和生长。其过量产生在多发性骨髓瘤和绝经后骨质疏松症的发病机理中起主要作用。在针对微生物产品中的IL-6抑制剂进行筛选的过程中，我们发现了马丹多林A（MDL-A）和马丹多林B，它们具有富二氢吲哚结构，二酮环戊烯键合到甲基上。MDL-A没有细胞毒活性。它仅抑制IL-6和IL-11的活性，而不会影响IL-6特异性信号转导级联反应JAK2 / STAT3。[（3）H] MDL-A以剂量依赖性方式与gp130结合，后者是一种信号转导的130 kDa糖蛋白，但三聚体复合物IL-6 / IL-6受体/ gp130的形成没有受到抑制，提示MDL-A抑制三聚体复合物的二聚化。在体外更年期骨质疏松的实验模型中，MDL-A不仅在体外显着抑制IL-6-和IL-11-诱导的破骨细胞生成，而且还抑制IL-6刺激的血清淀粉样蛋白A的产生和骨吸收。机理与17β-雌二醇有关。在这里，我们显示MDL-A通过抑制gp130活性同时抑制去卵巢小鼠的骨质流失，对IL-6和IL-11活性具有高度选择性的抑制作用。预期MDL-A是治疗激素依赖性绝经后骨质疏松症的主要化合物，它没有严重的副作用，gp130阻断是一种新的作用机制。但在绝经后骨质疏松症的体内实验模型中，它也通过与17β-雌二醇不同的机制抑制了IL-6刺激的血清淀粉样蛋白A的产生和骨吸收。在这里，我们显示MDL-A通过抑制gp130活性同时抑制去卵巢小鼠的骨质流失，对IL-6和IL-11活性具有高度选择性的抑制作用。预期MDL-A是治疗激素依赖性绝经后骨质疏松症的主要化合物，它没有严重的副作用，gp130阻断是一种新的作用机制。但在绝经后骨质疏松症的体内实验模型中，它也通过与17β-雌二醇不同的机制抑制了IL-6刺激的血清淀粉样蛋白A的产生和骨吸收。在这里，我们显示MDL-A通过抑制gp130活性同时抑制去卵巢小鼠的骨质流失，对IL-6和IL-11活性具有高度选择性的抑制作用。预期MDL-A是治疗激素依赖性绝经后骨质疏松症的主要化合物，它没有严重的副作用，gp130阻断是一种新的作用机制。在这里，我们显示MDL-A通过抑制gp130活性同时抑制去卵巢小鼠的骨质流失，对IL-6和IL-11活性具有高度选择性的抑制作用。预期MDL-A是治疗激素依赖性绝经后骨质疏松症的主要化合物，它没有严重的副作用，gp130阻断是一种新的作用机制。在这里，我们显示MDL-A通过抑制gp130活性同时抑制去卵巢小鼠的骨质流失，对IL-6和IL-11活性具有高度选择性的抑制作用。预期MDL-A是治疗激素依赖性绝经后骨质疏松症的主要化合物，它没有严重的副作用，gp130阻断是一种新的作用机制。

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Suppression of bone resorption by madindoline A, a novel nonpeptide antagonist to gp130.

IL-6 is a multifunctional cytokine involved in regulation of differentiation, antibody production, and growth of certain types of tumor cells. Its excessive production plays a major role in pathogenesis of multiple myeloma and postmenopausal osteoporosis. In the course of a screening program aimed at IL-6 inhibitor from microbial products, we found madindoline A (MDL-A) and madindoline B, which have a fuloindoline structure with diketocyclopentene bound to the methyl group. MDL-A has no cytotoxic activities. It inhibited only activities of both IL-6 and IL-11 without affecting the IL-6-specific signal transduction cascade, JAK2/STAT3. In a dose-dependent manner [(3)H]MDL-A binds to gp130, which is a signal transducing 130-kDa glycoprotein, but formation of the trimeric complex IL-6/IL-6 receptor/gp130 was not inhibited, suggesting that MDL-A suppresses dimerization of trimeric complexes. Not only did MDL-A markedly inhibit IL-6- and IL-11-induced osteoclastogenesis in vitro, but it also inhibited IL-6-stimulated serum amyloid A production and bone resorption in an experimental model of postmenopausal osteoporosis in vivo by a different mechanism from that of 17beta-estradiol. Here we show that MDL-A has a highly selective inhibitory effect on IL-6 and IL-11 activities by inhibiting a gp130 activity while suppressing bone loss in ovariectomized mice. MDL-A is anticipated as a lead compound for treatment of hormone-dependent postmenopausal osteoporosis, which has no serious side effects, and as a new mechanism of action, gp130 blocking.

更新日期：2017-01-31

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