title: The cellular actions of interleukin-11 on bone resorption in vitro.
abstract: 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.
authors.affiliation: Department of Orthodontics, United Medical and Dental Schools of Guy's and St. Thomas' Hospitals, University of London, United Kingdom.
authors.forename: P A
authors.initials: PA
authors.lastname: Hill
authors.forename: A
authors.initials: A
authors.lastname: Tumber
authors.forename: S
authors.initials: S
authors.lastname: Papaioannou
authors.forename: M C
authors.initials: MC
authors.lastname: Meikle
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D016718:Arachidonic Acid / Q000378:metabolism; D001854:Bone Marrow Cells / Q000502:physiology; D001862:Bone Resorption; D001842:Bone and Bones / Q000196:embryology; D002132:Calcium Radioisotopes / Q000378:metabolism; D002459:Cell Fusion; D002465:Cell Movement; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004351:Drug Resistance; D006801:Humans; D017370:Interleukin-11 / Q000008:administration & dosage / Q000494:pharmacology*; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000502:physiology; D010010:Osteoclasts / Q000502:physiology; D013644:Tartrates / Q000494:pharmacology
chemical_list: D002132:Calcium Radioisotopes; D017370:Interleukin-11; D013644:Tartrates; D016718:Arachidonic Acid; D003094:Collagen; D000135:Acid Phosphatase; D008666:Metalloendopeptidases; C029768:tartaric acid