Analysis of signal transduction of inflammatory cytokines in bone destruction

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The mechanism of osteoclastogenesis induced by lipopolysaccharide (LPS) was studied in cocultures of mouse osteoblasts and bone marrow cells. LPS stimulated osteoclastogenesis and prostaglandin E_2 (PGE_2) production in the cocultures, both of which were inhibited by NS398, a cyclooxygenase-2 inhibitor. LPS stimulated receptor activator of NF-κB ligand (RANKL) mRNA expression, and inhibited osteoprotegerin (OPG) mRNA expression in osteoblasts. NS398 inhibited only LPS-induced down-regulation of OPG mRNA expression, suggesting that LPS-stimulated PGE_2 production is important for the down-regulation of OPG. Indeed, NS398 failed to inhibit LPS-induced osteoclastogenesis in cocultures containing OPG knockout mouse-derived osteoblasts. Calcium/protein kinase C (PKC) inhibitors and PD98059 [mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor] suppressed RANKL mRNA expression in osteoblasts, and inhibited osteoclastogenesis in the cocultures treated with LPS. LPS induced phosphorylation of MEK and ERK in osteoblasts, and this induction was inhibited by calcium/PKC inhibitors. In addition, PD98059 and NS398 inhibited interleukin 1 (IL-1)-induced osteoclastogenesis in the cocultures, but only PD98059 suppressed RANKL mRNA expression induced by IL-1 in osteoblasts. These results suggest that LPS and IL-1 similarly promote osteoclastogenesis through two parallel events : enhancement of RANKL expression through calcium/PKC signals followed by MEK/ERK signals, and suppression of OPG production mediated by PGE_2.