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

Cited 77 time in scopus
Metadata Downloads
Title
Suppression of bone resorption by madindoline A, a novel nonpeptide antagonist to gp130
Author(s)
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
2002
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
Publisher
Natl Acad Sciences
DOI
http://dx.doi.org/10.1073/pnas.232562799
Type
Article
Appears in Collections:
Jeonbuk Branch Institute > Functional Biomaterial Research Center > 1. Journal Articles
Files in This Item:
  • There are no files associated with this item.


Items in OpenAccess@KRIBB are protected by copyright, with all rights reserved, unless otherwise indicated.