Reveromycin A, an Agent for Osteoporosis, Inhibits Bone Resorption by Inducing Apoptosis Specifically in Osteoclasts

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 12; pp. 4729 - 4734
• Main Authors: Woo, Je-Tae, Kawatani, Makoto, Kato, Masanori, Shinki, Toshimasa, Yonezawa, Takayuki, Kanoh, Naoki, Nakagawa, Hiroshi, Takami, Masamichi, Lee, Kun Hyung, Stern, Paula H., Nagai, Kazuo, Osada, Hiroyuki
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 21.03.2006; National Acad Sciences
• Subjects: Acids - pharmacology; Animals; Apoptosis; Biological Sciences; Bone and Bones - drug effects; Bone and Bones - pathology; Bone resorption; Bone Resorption - drug therapy; Bones; Cell lines; Culture Media - pharmacology; Cultured cells; Enzymes; Female; Isoleucine-tRNA Ligase - antagonists & inhibitors; Mice; Mice, Inbred Strains; Osteoclasts; Osteoclasts - cytology; Osteoclasts - drug effects; Osteoporosis; Osteoporosis - drug therapy; Pharmacology; Progenitor cells; Protein Biosynthesis - drug effects; Protein synthesis; Pyrans - therapeutic use; Rats; Rats, Sprague-Dawley; Ribonucleic acid; RNA; Spiro Compounds - therapeutic use
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0505663103

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.