Suppression of bone resorption by madindoline A, a novel nonpeptide antagonist to gp130

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  • Masahiko Hayashi
    Kitasato Institute for Life Sciences and School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Cardiovascular Research Laboratory, Korea Research Institute of Bioscience and Biotechnology, Taejon 305-333, Korea; and The Kitasato Institute, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan
  • Mun-Chual Rho
    Kitasato Institute for Life Sciences and School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Cardiovascular Research Laboratory, Korea Research Institute of Bioscience and Biotechnology, Taejon 305-333, Korea; and The Kitasato Institute, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan
  • Akiko Enomoto
    Kitasato Institute for Life Sciences and School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Cardiovascular Research Laboratory, Korea Research Institute of Bioscience and Biotechnology, Taejon 305-333, Korea; and The Kitasato Institute, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan
  • Akiko Fukami
    Kitasato Institute for Life Sciences and School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Cardiovascular Research Laboratory, Korea Research Institute of Bioscience and Biotechnology, Taejon 305-333, Korea; and The Kitasato Institute, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan
  • Yong-Pil Kim
    Kitasato Institute for Life Sciences and School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Cardiovascular Research Laboratory, Korea Research Institute of Bioscience and Biotechnology, Taejon 305-333, Korea; and The Kitasato Institute, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan
  • Yuji Kikuchi
    Kitasato Institute for Life Sciences and School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Cardiovascular Research Laboratory, Korea Research Institute of Bioscience and Biotechnology, Taejon 305-333, Korea; and The Kitasato Institute, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan
  • Toshiaki Sunazuka
    Kitasato Institute for Life Sciences and School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Cardiovascular Research Laboratory, Korea Research Institute of Bioscience and Biotechnology, Taejon 305-333, Korea; and The Kitasato Institute, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan
  • Tomoyasu Hirose
    Kitasato Institute for Life Sciences and School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Cardiovascular Research Laboratory, Korea Research Institute of Bioscience and Biotechnology, Taejon 305-333, Korea; and The Kitasato Institute, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan
  • Kanki Komiyama
    Kitasato Institute for Life Sciences and School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Cardiovascular Research Laboratory, Korea Research Institute of Bioscience and Biotechnology, Taejon 305-333, Korea; and The Kitasato Institute, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan
  • Satoshi Omura
    Kitasato Institute for Life Sciences and School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Cardiovascular Research Laboratory, Korea Research Institute of Bioscience and Biotechnology, Taejon 305-333, Korea; and The Kitasato Institute, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan

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<jats:p>IL-6 is a multifunctional cytokine involved in regulation of differentiation, antibody production, and growth of certain types of tumor cells. Its excessive production plays a major role in pathogenesis of multiple myeloma and postmenopausal osteoporosis. In the course of a screening program aimed at IL-6 inhibitor from microbial products, we found madindoline A (MDL-A) and madindoline B, which have a fuloindoline structure with diketocyclopentene bound to the methyl group. MDL-A has no cytotoxic activities. It inhibited only activities of both IL-6 and IL-11 without affecting the IL-6-specific signal transduction cascade, JAK2/STAT3. In a dose-dependent manner [<jats:sup>3</jats:sup>H]MDL-A binds to gp130, which is a signal transducing 130-kDa glycoprotein, but formation of the trimeric complex IL-6/IL-6 receptor/gp130 was not inhibited, suggesting that MDL-A suppresses dimerization of trimeric complexes. Not only did MDL-A markedly inhibit IL-6- and IL-11-induced osteoclastogenesis<jats:italic>in vitro</jats:italic>, but it also inhibited IL-6-stimulated serum amyloid A production and bone resorption in an experimental model of postmenopausal osteoporosis<jats:italic>in vivo</jats:italic>by a different mechanism from that of 17β-estradiol. Here we show that MDL-A has a highly selective inhibitory effect on IL-6 and IL-11 activities by inhibiting a gp130 activity while suppressing bone loss in ovariectomized mice. MDL-A is anticipated as a lead compound for treatment of hormone-dependent postmenopausal osteoporosis, which has no serious side effects, and as a new mechanism of action, gp130 blocking.</jats:p>

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