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Objectives: The receptor activator of nuclear factor-κB ligand (RANKL), as a member of the tumor necrosis factor (TNF) family, plays an essential role in osteoclast differentiation and function.The purpose of this study was to examine the effects of RANKL on CXCR6 expression in osteoclast precursor cells, RAW264.7cells.Methods: RAW264.7 cells were treated with RANKL, and the expression of CXCR6 protein was determined using flow cytometry and Western blotting.The migrating and adhesive ability of RANKL-stimulated RAW264.7 cells were measured by chemotaxis assay and cell adheresion assay respectively.The levels of RANK and osteoclastogenic markers were examined using reverse transcriptase polymerase chain reaction.RAW264.7 cells were cocultured with or without CXCL-16 and macrophage colony-stimulating factor, and osteoclastogenesis was assessed by counting the multinucleated cells (those staining positive for tartrate-resistant acid phosphatase).Results: CXCL16 receptor, membrane CXCR6 expression, was reduced by treatment with RANKL in contrast to the increased mRNA expression of cathepsin-k and tartrate-resistant acid phosphatase (TRAP).This reduction was dose-dependent from 10 ng/mL to 100 ng/mL RANKL stimulation.And the total CXCR6 protein expression was also decreased at 100 ng/mL RANKL stimulation for 48h.The down-regulation of CXCR6 expression correlated with the suppression of CXCL16-induced activation of Akt and ERK.Furthermore, We confirmed that the migration or adhesion ability of RANKL stimulated RAW264.7 cells were decreased under the soluble CXCL16 chemotaxis.However, there is no direct effect of CXCL16 stimulation on RANK expression and osteoclastogenesis of RAW264.7 cells.Conclusion: These results suggest a potential role for decreased CXC16-CXCR6 interaction in osteoclastogenesis.The CXCL 16-CXCR6 axis may be a novel target for the therapeutic intervention of bone resorbing diseases such as rheumatoid arthritis and osteoporosis.