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Title 

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

Authors 

M HayashiMun Chual RhoA EnomotoA FukamiY P KimY KikuchiT SunazukaT HiroseK KomiyamaS Omura

Publisher 

National Academy of Sciences

Issue Date 

2002

Citation 

Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 23, pp. 14728-14733

Keywords 

janus kinasemadindoline Amadindoline BSTAT3 proteinunclassified druganimal cellanimal experimentanimal modelantibody productiondimerization

Abstract 

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.

ISSN 

0027-8424

Link 

http://dx.doi.org/10.1073/pnas.232562799

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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