Suppression of bone resorption by madindoline A, a novel nonpeptide antagonist to gp130
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- Suppression of bone resorption by madindoline A, a novel nonpeptide antagonist to gp130
- M Hayashi; Mun Chual Rho; A Enomoto; A Fukami; Y P Kim; Y Kikuchi; T Sunazuka; T Hirose; K Komiyama; S Omura
- Bibliographic Citation
- Proceedings of National Academy of Sciences of United States of America, vol. 99, no. 23, pp. 14728-14733
- Publication Year
- 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 [3H]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 in vitro, but it also inhibited IL-6-stimulated serum amyloid A production and bone resorption in an experimental model of postmenopausal osteoporosis in vivo 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.
- Natl Acad Sciences
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- Jeonbuk Branch Institute > Functional Biomaterial Research Center > 1. Journal Articles
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