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

• Je-Tae Woo

  *Department of Biological Chemistry, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501, Japan;

• Makoto Kawatani

  Antibiotics Laboratory, Discovery Research Institute, RIKEN, Hirosawa 2-1, Wako, Saitama 351-0198, Japan;

• Masanori Kato

  Department of Bioengineering, Tokyo Institute of Technology, 4259 Nagatsuda-cho, Midori-ku, Yokohama 226-8501, Japan;

• Toshimasa Shinki

  Department of Biochemistry, Nihon Pharmaceutical University, 10281 Komuro, Ina-cho, Kitaadachi-gun, Saitama 362-0806, Japan; and

• Takayuki Yonezawa

  *Department of Biological Chemistry, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501, Japan;

• Naoki Kanoh

  Antibiotics Laboratory, Discovery Research Institute, RIKEN, Hirosawa 2-1, Wako, Saitama 351-0198, Japan;

• Hiroshi Nakagawa

  Department of Bioengineering, Tokyo Institute of Technology, 4259 Nagatsuda-cho, Midori-ku, Yokohama 226-8501, Japan;

• Masamichi Takami

  Department of Bioengineering, Tokyo Institute of Technology, 4259 Nagatsuda-cho, Midori-ku, Yokohama 226-8501, Japan;

• Kun Hyung Lee

  *Department of Biological Chemistry, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501, Japan;

• Paula H. Stern

  **Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611

• Kazuo Nagai

  *Department of Biological Chemistry, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501, Japan;

• Hiroyuki Osada

  Antibiotics Laboratory, Discovery Research Institute, RIKEN, Hirosawa 2-1, Wako, Saitama 351-0198, Japan;

抄録

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.

収録刊行物

• Proceedings of the National Academy of Sciences

  Proceedings of the National Academy of Sciences 103 (12), 4729-4734, 2006-03-13

  Proceedings of the National Academy of Sciences

キーワード

• Multidisciplinary

詳細情報

• CRID: 1361699996321991040
• NII論文ID: 80019247588
• DOI: 10.1073/pnas.0505663103
• ISSN: 10916490
• ISSN: 00278424
• Web Site: https://pnas.org/doi/pdf/10.1073/pnas.0505663103
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