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The Cellular Actions of Interleukin-11 on Bone Resorption in Vitro

Departments of Orthodontics and Pediatric Dentistry (P.A.H., M.C.M.) and Craniofacial Biology (A.T., S.P.), United Medical and Dental Schools of Guy’s and St. Thomas’ Hospitals, University of London, London, United Kingdom SE1 9RT

Address all correspondence and requests for reprints to: Dr. Peter A. Hill, Department of Orthodontics and Pediatric Dentistry, United Medical and Dental Schools of Guy’s and St. Thomas’ Hospitals, London Bridge, London, United Kingdom SE1 9RT.

The pleiotropic cytokine interleukin-11 (IL-11) stimulates osteoclast formation in vitro, but it is not known whether it influences other steps 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 matrix metalloproteinases (MMPs) and products of arachidonic acid metabolism in IL-11-mediated resorption were also assessed.

We first examined the bone-resorptive effects of IL-11 by assessing ⁴⁵Ca release from neonatal mouse calvarial bones. IL-11 dose-dependently stimulated bone resorption with an EC₅₀ of 10^-10 M. The kinetics of IL-11-mediated ⁴⁵Ca release demonstrated that it was without effect for the first 48 h of culture, but by 96 h, it stimulated ⁴⁵Ca release to the same level as that produced by 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃] (a hormone that stimulates osteoclast formation and activity). IL-11 also produced a dose-dependent increase in osteoblast-mediated type I collagen degradation with a maximum of 58.0 ± 6.2% at 5 x 10^-9 M; this effect of IL-11 was less than that produced by 1,25-(OH)₂D₃ (76.5 ± 7.1%) and was prevented by an inhibitor of MMPs, but not those blocking arachidonic acid metabolism. We then tested the effects of IL-11 on isolated mouse osteoclasts cultured on ivory slices in the presence and absence of primary mouse osteoblasts. IL-11 had no effect on isolated osteoclast activity even in coculture with primary osteoblasts. We then examined the effects of IL-11 on the formation of osteoclast-like multinucleate cells in mouse bone marrow cultures and the resorptive activity of such cultures using ivory as a substrate. IL-11 dose-dependently increased 1) the number of tartrate-resistant acid phosphatase-positive osteoclast-like multinucleate cells and 2) the surface area of lacunar resorption, although the effects were less than that of 1,25-(OH)₂D₃. The effect of IL-11 on bone marrow lacunar resorption was prevented by a combination of inhibitors of 5-lipoxygenase and cyclooxygenase. In 17-day-old metatarsal bones, IL-11 prevented the migration 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 osteoblast-mediated osteoid degradation rather than stimulating osteoclast migration and activity. Our data also suggest that the stimulatory effects of IL-11 involve both MMPs and products of arachidonic acid metabolism.

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