Reveromycin A, an agent for osteoporosis, inhibits bone resorption by inducing apoptosis specifically in osteoclasts.
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.
Woo
Je-Tae
JT
Department of Biological Chemistry, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501, Japan. jwoo@isc.chubu.ac.jp
Kawatani
Makoto
M
Kato
Masanori
M
Shinki
Toshimasa
T
Yonezawa
Takayuki
T
Kanoh
Naoki
N
Nakagawa
Hiroshi
H
Takami
Masamichi
M
Lee
Kun Hyung
KH
Stern
Paula H
PH
Nagai
Kazuo
K
Osada
Hiroyuki
H
D000143:Acids / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D001862:Bone Resorption / Q000188:drug therapy*; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology; D003470:Culture Media / Q000494:pharmacology; D005260:Female; D007533:Isoleucine-tRNA Ligase / Q000037:antagonists & inhibitors; D051379:Mice; D008815:Mice, Inbred Strains; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D010024:Osteoporosis / Q000188:drug therapy*; D014176:Protein Biosynthesis / Q000187:drug effects; D011714:Pyrans / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000627:therapeutic use*
D000143:Acids; D003470:Culture Media; D011714:Pyrans; D013141:Spiro Compounds; C068098:reveromycin A; D007533:Isoleucine-tRNA Ligase