DEPENDENCY OF OSTEOCLAST DIFFERENTIATION ON EXOGENOUS CHOLESTEROL AND ROLE OF CAVEOLIN-1 IN OSTEOCLASTOGENESIS

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To elucidate the cellular and molecular mechanisms underlying the high dependency of osteoclastogenesis on exogenous cholesterol and the role of a major scaffold protein in lipid rafts, caveolin-1(Cav-1), in osteoclast differentiation, we examined in vitro osteoclast formation and in vivo bone morphometrical analysis using low-density lipoprotein receptor(LDLR) knockout(KO) and Cav-1 mice. In this study, we found that osteoclast formation strictly required the uptake of exogenous cholesterol via LDLR and that LDLR deficiency causes impaired osteoclastogenesis and increased bone mass in mice because of defect in osteoclastic cell-cell fusion. In addition, in vitro osteoclastogenesis of precursor cells from Cav-1-null mice was comparable to that of wild-type mice, while Cav-2 expression in the knockout osteoclasts was maintained. Conversely, Cav-2 gene silencing in Cav-1-null osteoclast precursors using siRNA for Cav-2 increased osteoclast formation, suggesting that the Cav-1/Cav-2 complex may acts as a negative regulator for osteoclastogenesis. Taken together, these findings provide a novel mechanism for osteoclast differentiation and improve the understanding of the correlation between osteoclast formation and lipids.