THE CELLULAR ACTIONS OF INTERLEUKIN-11 ON BONE-RESORPTION IN-VITRO

The pleiotropic cytokine interleukin-11 (IL-11) stimulates osteoclast formation in. vitro, but it is not known whether it influences other s teps in the bone-resorptive cascade. Using a variety of in vitro model systems for studying bone resorption we have investigated the effects of IL-11 on 1) osteoclast formation, fusion, migration, and activity; and 2) osteoblast-mediated osteoid degradation. The involvement of ma trix metalloproteinases (MMPs) and products of arachidonic acid metabo lism in IL-11-mediated resorption were also assessed. We first examine d the bone-resorptive effects of IL-11 by assessing Ca-45 release from neonatal mouse calvarial bones. IL-11 dose-dependently stimulated bon e resorption with an EC50 of 10(-10) hr. The kinetics of IL-11-mediate d Ca-45 release demonstrated that it was without effect for the first 48 h of culture, but by 96 h, it stimulated Ca-45 release to the same level as that produced by 1,25-dihydroxyvitamin D-3 [1,25-(OH)(2)D-3] (a hormone that stimulates osteoclast formation and activity). IL-11 a lso produced a dose-dependent increase in osteoblast-mediated type I c ollagen degradation with a maximum of 58.0 +/- 6.2% at 5 x 10(-9) ra; this effect of IL-11 was less than that produced by 1,25-(OH)(2)D-3 (7 6.5 +/- 7.1%) and was prevented by an inhibitor of MMPs, but not those blocking arachidonic acid metabolism. We then tested the effects of I L-11 on isolated mouse osteoclasts cultured on ivory slices in the pre sence and absence of primary mouse osteoblasts. IL-11 had no effect on isolated osteoclast activity even in coculture with primary osteoblas ts. We then examined the effects of IL-11 on the formation of osteocla st-like multinucleate cells in mouse bone marrow cultures and the reso rptive activity of such cultures using ivory as a substrate. IL-11 dos e-dependently increased 1) the number of tartrate-resistant acid phosp hatase-positive osteoclastlike multinucleate cells and 2) the surface area of lacunar resorption, although the effects were less than that o f 1,25-(OH)(2)D-3. The effect of IL-ll on bone marrow lacunar resorpti on was prevented by a combination of inhibitors of Ei-Lipoxygenase and cyclooxygenase. In 17-day-old metatarsal bones, IL-11 prevented the m igration of (pre)osteoclasts to future resorption sites, whereas their fusion was unaffected. These results provide strong evidence that IL- 11 stimulates bone resorption by enhancing osteoclast formation and os teoblast-mediated osteoid degradation rather than stimulating osteocla st migration and activity. Our data also suggest that the stimulatory effects of IL-11 involve both MMPs and products of arachidonic acid me tabolism.