| 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
|
| リソース情報 |
| ヒト・動物細胞 |
RAW 264(RCB0535) |
