The roles of TNFR1 in lipopolysaccharide-induced bone loss: dual effects of TNFR1 on bone metabolism via osteoclastogenesis and osteoblast survival.

Abstract

LPS (lipopolysaccharide), a major constituent of Gram-negative bacteria, regulates proliferation and differentiation of osteoclasts directly or indirectly. This study sought to investigate the functions of the RANK/RANKL pathway in LPS-induced bone loss in vivo. Wild-type mice or TNFR1-/- mice were injected LPS with or without osteoprotegerin (OPG) and analyzed histologically. Bone volume was reduced by LPS injection in all groups, and OPG administration prevented the LPS-induced bone loss regardless of genotypes. LPS-induced enhancement of osteoclastogenesis in wild-type mice was blocked by OPG administration. LPS or OPG did not affect osteoclastogenesis in TNFR1-/- mice. Interestingly, osteoblast surface was remarkably reduced in LPS-treated TNFR1-/- mice as a result of enhanced osteoblast apoptosis. TRAIL, induced by TNF-alpha in BMC, triggered apoptosis of primary osteoblast only when TNFR1 signal was ablated in vitro. In conclusion, RANK signaling plays a prominent role in osteoclastogenesis downstream of LPS. Furthermore, TNFR1 regulates bone metabolism through not only the regulation of osteoclast differentiation but also osteoblast survival.