{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T13:19:13Z","timestamp":1791206353206,"version":"4.1.0"},"reference-count":38,"publisher":"National Academy of Sciences","issue":"23","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2002,11,12]]},"abstract":"<jats:p>\n                    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 [\n                    <jats:sup>3<\/jats:sup>\n                    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\n                    <jats:italic>in vitro<\/jats:italic>\n                    , but it also inhibited IL-6-stimulated serum amyloid A production and bone resorption in an experimental model of postmenopausal osteoporosis\n                    <jats:italic>in vivo<\/jats:italic>\n                    by a different mechanism from that of 17\u03b2-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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.232562799","type":"journal-article","created":{"date-parts":[[2002,11,12]],"date-time":"2002-11-12T13:44:20Z","timestamp":1037108660000},"page":"14728-14733","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":82,"title":["Suppression of bone resorption by madindoline A, a novel nonpeptide antagonist to gp130"],"prefix":"10.1073","volume":"99","author":[{"given":"Masahiko","family":"Hayashi","sequence":"first","affiliation":[{"name":"Kitasato Institute for Life Sciences and School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Cardiovascular Research Laboratory, Korea Research Institute of Bioscience and Biotechnology, Taejon 305-333, Korea; and The Kitasato Institute, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mun-Chual","family":"Rho","sequence":"additional","affiliation":[{"name":"Kitasato Institute for Life Sciences and School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; 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