Reveromycin A, an agent for osteoporosis, inhibits bone resorption by inducing apoptosis specifically in osteoclasts
Reveromycin A, an agent for osteoporosis, inhibits bone resorption by inducing apoptosis specifically in osteoclasts
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DOI：
10.1073/pnas.0505663103
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发表时间：
2006-03-21
影响因子：
11.1
通讯作者：
Osada, H
中科院分区：
文献类型：
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作者：
Woo, JT;Kawatani, M;Osada, H
成熟的骨再吸收破骨细胞（OC）介导在包括骨质疏松症在内的几种骨疾病中观察到的过度骨丢失。在这里，我们发现，回复霉素A（RM-A），一个小的天然产物，其结构中的三个羧基，诱导细胞凋亡，特别是在OC，但不是在OC祖细胞，无功能的破骨细胞，或成骨细胞。RM-A通过选择性地阻断异亮氨酰-tRNA合成酶的酶活性来抑制OC中的蛋白质合成。RM-A的促凋亡作用被抑制的中和或破坏的酸性微环境，一个突出的特点OC。在中性培养液中，RM-A被纳入OC中，但不被纳入无功能破骨细胞和OC祖细胞中。在酸性培养条件下，RM-A对OC凋亡的影响增强。在酸性培养基中，RM-A不仅掺入OC祖细胞，而且诱导OC祖细胞凋亡。RM-A抑制骨陷窝的形成，减少器官培养物中的预标记Ca-45释放，并拮抗卵巢切除小鼠骨吸收的增加。这些结果表明，RM-A在体外和体内对骨吸收的预防作用是通过抑制OCs中的异亮氨酰-tRNA合成酶而引起的细胞凋亡，并且OCs对RM-A的特异性敏感性是由于酸性微环境，其通过抑制质子从羧酸部分的解离而增加了RM-A的细胞渗透性，使其极性降低。这种独特的机制表明，RM-A可能代表一种治疗与骨丢失增加相关的骨疾病的治疗剂。
Mature bone-resorbing osteoclasts (OCs) mediate excessive bone loss seen in several bone disorders, including osteoporosis. Here, we showed that reveromycin A (RM-A), a small natural product with three carboxylic groups in its structure, induced apoptosis specifically in OCs, but not in OC progenitors, nonfunctional osteoclasts, or osteoblasts. RM-A inhibited protein synthesis in OCs by selectively blocking enzymatic activity of isoleucyl-tRNA synthetase. The proapoptotic effect of RM-A was inhibited by neutralization or disruption of the acidic microenvironment, a prominent characteristic of OCs. RM-A was incorporated in OCs but not in nonfunctional osteoclasts and OC progenitors in neutral culture medium. Effects of RM-A on OC apoptosis increased under acidic culture conditions. RM-A not only was incorporated, but also induced apoptosis in OC progenitors in acidic culture medium. RM-A inhibited osteoclastic pit formation, decreased prelabeled Ca-45 release in organ cultures, and antagonized increased bone resorption in ovariectomized mice. These results suggested that preventive effects of RM-A on bone resorption in vitro and in vivo were caused by apoptosis through inhibition of isoleucyl-tRNA synthetase in OCs and that specific sensitivity of OCs to RM-A was due to the acidic microenvironment, which increased cell permeability of RM-A by suppressing dissociation of protons from carboxylic acid moieties, making them less polar. This unique mechanism suggested that RM-A might represent a type of therapeutic agent for treating bone disorders associated with increased bone loss.