Suppression of bone resorption by madindoline A, a novel nonpeptide antagonist to gp130.
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.
Hayashi
Masahiko
M
Kitasato Institute for Life Sciences and School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Rho
Mun-Chual
MC
Enomoto
Akiko
A
Fukami
Akiko
A
Kim
Yong-Pil
YP
Kikuchi
Yuji
Y
Sunazuka
Toshiaki
T
Hirose
Tomoyasu
T
Komiyama
Kanki
K
Omura
Satoshi
S
D000818:Animals; D001862:Bone Resorption / Q000517:prevention & control*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D016209:Interleukin-8; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D020932:Nerve Growth Factor / Q000494:pharmacology; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism; D015534:Trans-Activators / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D019086:Bridged Bicyclo Compounds, Heterocyclic; D016207:Cytokines; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D007211:Indoles; D007376:Interleukin-2; D007377:Interleukin-3; D015850:Interleukin-6; D016209:Interleukin-8; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D018121:Receptors, Cytokine; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; C456339:cytokine receptor, GLM-R; C103158:madindoline A; D015847:Interleukin-4; D020932:Nerve Growth Factor