論文 - 詳細
| RRC ID | 42586 |
|---|---|
| 著者 | Woo JT, Kawatani M, Kato M, Shinki T, Yonezawa T, Kanoh N, Nakagawa H, Takami M, Lee KH, Stern PH, Nagai K, Osada H. |
| タイトル | Reveromycin A, an agent for osteoporosis, inhibits bone resorption by inducing apoptosis specifically in osteoclasts. |
| ジャーナル | Proc Natl Acad Sci U S A |
| Abstract |
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 (45)Ca 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. |
| 巻・号 | 103(12) |
| ページ | 4729-34 |
| 公開日 | 2006-3-21 |
| DOI | 10.1073/pnas.0505663103 |
| PII | 0505663103 |
| PMID | 16537392 |
| PMC | PMC1450238 |
| MeSH | Acids / pharmacology Animals Apoptosis* Bone Resorption / drug therapy* Bone and Bones / drug effects Bone and Bones / pathology Culture Media / pharmacology Female Isoleucine-tRNA Ligase / antagonists & inhibitors Mice Mice, Inbred Strains Osteoclasts / cytology Osteoclasts / drug effects* Osteoporosis / drug therapy* Protein Biosynthesis / drug effects Pyrans / therapeutic use* Rats Rats, Sprague-Dawley Spiro Compounds / therapeutic use* |
| IF | 9.412 |
| 引用数 | 58 |
| WOS 分野 | ENDOCRINOLOGY & METABOLISM |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 4 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | RAW 264(RCB0535) |