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.
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Authors | 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 |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 103
Issue 12
Pg. 4729-34
(Mar 21 2006)
ISSN: 0027-8424 [Print] United States |
PMID | 16537392
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Acids
- Culture Media
- Pyrans
- Spiro Compounds
- reveromycin A
- Isoleucine-tRNA Ligase
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Topics |
- Acids
(pharmacology)
- Animals
- Apoptosis
- Bone Resorption
(drug therapy)
- Bone and Bones
(drug effects, pathology)
- Culture Media
(pharmacology)
- Female
- Isoleucine-tRNA Ligase
(antagonists & inhibitors)
- Mice
- Mice, Inbred Strains
- Osteoclasts
(cytology, drug effects)
- Osteoporosis
(drug therapy)
- Protein Biosynthesis
(drug effects)
- Pyrans
(therapeutic use)
- Rats
- Rats, Sprague-Dawley
- Spiro Compounds
(therapeutic use)
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