ABSTRACT
TNF-alpha is a major etiologic factor of inflammatory bone diseases such as periodontitis and rheumatoid arthritis. In addition, patients with metabolic diseases such as chronic heart disease and diabetes have significantly increased plasma levels of TNF-alpha. Several lines of evidence show inhibition of osteoblastogenesis by TNF-alpha in vitro. Therefore, bone formation and osteogenesis in these patients might be inhibited because of TNF-alpha. However, little is known about the inhibitory role of TNF-alpha in bone formation/osteogenesis in vivo. The purpose of this study was to investigate the role of TNF-alpha in osteogenesis using a murine tooth extraction model. Lipopolysaccharide (LPS) was injected subcutaneously into the calvariae of either wildtype (WT) or TNF-alpha-deficient (KO) mice. The left incisor was extracted 4 days after LPS injection. The measuring area was established as the tooth socket under the mesial root of the first molar. A significant increase in serum TNF-alpha levels after LPS injection was observed in WT mice. The BMD of the tooth socket was significantly decreased by LPS injection 21 days after extraction in WT but not in KO mice. Histomorphometric analysis showed a significant decrease in the mineral apposition rate after LPS injection, which appeared at an early stage in WT but not in KO mice. Injection of a peptide that blocked the TNF-alpha signaling pathway by preventing transmission of the NF-kappaB signal recovered the inhibition of osteogenesis observed after LPS injection. In conclusion, TNF-alpha might play a major role in LPS-induced inhibition of osteogenesis under inflammatory conditions.
