Reveromycin A, an agent for osteoporosis, inhibits bone resorption by inducing apoptosis specifically in osteoclasts

Je Tae Woo, Makoto Kawatani, Masanori Kato, Toshimasa Shinki, Takayuki Yonezawa, Naoki Kanoh, Hiroshi Nakagawa, Masamichi Takami, Kun Hyung Lee, Paula H. Stern, Kazuo Nagai, Hiroyuki Osada

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)

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 45Ca 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.

Original languageEnglish
Pages (from-to)4729-4734
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number12
DOIs
Publication statusPublished - 2006 Mar 21

Keywords

  • Antiresorptive agent
  • Inhibitor
  • Isoleucyl-tRNA synthetase

ASJC Scopus subject areas

  • General

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