, 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, JAK2͞STAT3. 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-6͞IL-6 receptor͞gp130 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 17␤-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.

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