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

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 [(3)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 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 17beta-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.

• Authors: Masahiko Hayashi, Mun-Chual Rho, Akiko Enomoto, Akiko Fukami, Yong-Pil Kim, Yuji Kikuchi, Toshiaki Sunazuka, Tomoyasu Hirose, Kanki Komiyama, Satoshi Omura
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 99 Issue 23 Pg. 14728-33 (Nov 12 2002) ISSN: 0027-8424 [Print] United States
• PMID: 12417753 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• Cytokines
• DNA-Binding Proteins
• Growth Inhibitors
• Indoles
• Interleukin-2
• Interleukin-3
• Interleukin-6
• Interleukin-8
• LIF protein, human
• Leukemia Inhibitory Factor
• Lif protein, mouse
• Lymphokines
• Receptors, Cytokine
• Recombinant Proteins
• STAT3 Transcription Factor
• STAT3 protein, human
• Stat3 protein, mouse
• Trans-Activators
• Tumor Necrosis Factor-alpha
• cytokine receptor, GLM-R
• madindoline A
• Interleukin-4
• Nerve Growth Factor

Topics

• Animals
• Bone Resorption (prevention & control)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Line
• Cytokines (pharmacology)
• DNA-Binding Proteins (metabolism)
• Female
• Growth Inhibitors (pharmacology)
• Humans
• Indoles (pharmacology)
• Interleukin-2 (pharmacology)
• Interleukin-3 (pharmacology)
• Interleukin-4 (pharmacology)
• Interleukin-6 (pharmacology)
• Interleukin-8
• Leukemia Inhibitory Factor
• Lymphokines (pharmacology)
• Macrophages (drug effects, physiology)
• Mice
• Mice, Inbred C3H
• Mice, Inbred Strains
• Nerve Growth Factor (pharmacology)
• Receptors, Cytokine (antagonists & inhibitors)
• Recombinant Proteins (pharmacology)
• STAT3 Transcription Factor
• Signal Transduction (drug effects, physiology)
• Stereoisomerism
• Trans-Activators (metabolism)
• Tumor Necrosis Factor-alpha (pharmacology)