Interleukin-1 and tumor necrosis factor activities partially account for calvarial bone resorption induced by local injection of lipopolysaccharide

The present study was undertaken to test the hypothesis that tumor necrosis factor (TNF) and/or interleukin-1 (IL-1) activity mediates lipopolysacchar ide (LPS)-induced bone resorption in vivo. To test this hypothesis, Escheri chia coil LPS or Porphyromonas gingivalis LPS was injected into the subcuta neous tissues overlying mouse calvariae. Histological sections, prepared fr om the center of the lesion, were stained for tartrate-resistant acid phosp hatase, and histomorphometric analysis was performed to quantify the osteoc last number and the area of bone resorption. In time course experiments usi ng normal mice, a peak of bone resorption occurred 5 days after endotoxin s timulation. In dose-response experiments, IL-1 receptor type 1 deletion (IL -1R(-/-)), TNF double-receptor p55/p75 deletion (TNF p55(-/-)/p75(-/-)), co mbined TNF p55 and IL-1 receptor type 1 deletion (TNF p55(-/-)/IL-1R(-/-)), and IL-1 beta-converting enzyme-deficient (ICE-/-) mice and the respective wild-type mice were injected with 500, 100, or 20 mu g of P. gingivalis LP S and sacrificed 5 days after LPS injection. At the highest dose (500 mu g) , significant decreases in osteoclast number occurred in mutant mice compar ed to wild-type mice: (i) a 64% reduction for the TNF p55(-/-)/IL-1R(-/-) m ice, (ii) a 57% reduction for the IL-1R(-/-) mice, (iii) a 41% reduction fo r the TNF p55(-/-)/p75(-/-) mice, and (iv) a 38% reduction for the ICE-/- m ice. At the two lower doses, bone resorption was apparent but no significan t differences between mutant and wild-type animals were observed. The prese nt data indicate that at higher doses, LPS-induced bone resorption is subst antially mediated by IL-1 and TNF receptor signaling. Furthermore, IL-1 rec eptor signaling appears to be slightly more important than TNF receptor sig naling. At lower LPS doses, other pathways leading to osteoclast activity t hat are independent of TNF and IL-1 are involved.