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

• Published in: Endocrinology (Philadelphia) Vol. 139; no. 4; pp. 1564 - 1572
• Main Authors: Hill, Peter A, Tumber, Anthony, Papaioannou, Stelios, Meikle, Murray C
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01-04-1998; Oxford University Press
• Subjects: Acid phosphatase; Acid phosphatase (tartrate-resistant); Acid Phosphatase - metabolism; Acid resistance; Acids; Animals; Animals, Newborn; Arachidonate 5-lipoxygenase; Arachidonic acid; Arachidonic Acid - metabolism; Bone and Bones - embryology; Bone growth; Bone marrow; Bone Marrow Cells - physiology; Bone Resorption; Calcitriol; Calcium isotopes; Calcium Radioisotopes - metabolism; Cell culture; Cell Fusion; Cell Movement; Cells, Cultured; Collagen (type I); Collagen - metabolism; Cytokines; Degradation; Drug Resistance; Humans; Interleukin 11; Interleukin-11 - administration & dosage; Interleukin-11 - pharmacology; Interleukins; Lipoxygenase; Matrix metalloproteinase; Matrix metalloproteinases; Metabolism; Metalloendopeptidases - metabolism; Mice; Neonates; Osteoblasts; Osteoblasts - physiology; Osteoclasts; Osteoclasts - physiology; Osteoid; Prostaglandin endoperoxide synthase; Space life sciences; Tartrates - pharmacology; Vitamin D3
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/endo.139.4.5946

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 ×
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.