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

• DOI: 10.1073/pnas.232562799
• Publication Date: 2002-11-12T18:44:20Z
• Authors: Masahiko Hayashi; Mun-Chual Rho; Akiko Enomoto; Akiko Fukami; Yong-Pil Kim; Yuji Kikuchi; Toshiaki Sunazuka; Tomoyasu Hirose; Kanki Komiyama; Satoshi Omura
• Keywords: Glycoprotein 130

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