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Background/Aims: Non-small cell lung carcinoma (NSCLC) metastasis to bone leads to skeletal-related events and a poor quality of life. Unravelling the mechanism of metastasis is crucial for improving survival. Previous work has implicated the role of CXCR4 in bone metastasis; however, the underlying mechanisms are unknown. Methods: The human bone metastasis tissue samples were obtained from lung cancer patients during surgery with consents. The patients were followed up and the overall survival curve was analysed. The expression of CXCR4, VCAM1, and ADAM17 was measured with real-time PCR, western blot and immunochemistry staining in human tissue or NSCLC cell lines. The effects of CXCR4, soluble VCAM1 and ADAM17 on NSCLC proliferation, migration and invasion were measured with CCK-8, monolayer scratch assay and transwell chamber, respectively. The amount of soluble VCAM1 in the conditioned medium was detected with ELISA. Tartrate-resistant acid phosphatasethe (TRAP) staining was performed to stain the multinucleated cells regarded as osteoclasts. Results: In this study, CXCR4 was found to be highly expressed in bone destruction area of metastatic NSCLC samples and related to poor survival in NSCLC patients with bone metastasis. CXCR4 potentiated NSCLC with enhanced proliferation and invasion abilities, while CXCR4 knockdown significantly suppressed the growth and invasion. Furthermore, CXCR4 promoted lung cancer-induced osteoclast differentiation with increased osteoclast formation. We also found that soluble VCAM1 (sVCAM1) secreted in NSCLC contributed to the osteoclastogenesis induced by CXCR4. The overexpression of CXCR4 increased sVCAM1, and the sVCAM1 secreted from CXCR4-overexpressing NSCLC cells recruited and arrested additional osteoclast progenitors to promote osteoclastogenesis. ADAM17 was confirmed to act as a downstream mediator of CXCR4. The chemical inhibition of ADAM17 with TAPI-2 decreased sVCAM1 secretion and the number of TRAP+ osteoclasts. Conclusion: Taken together, these results indicated that CXCR4 potentiated NSCLC and promoted osteoclastogenesis through sVCAM1, which was cleaved by ADAM17. These data support the pivotal role of the cross talk between CXCR4 and ADAM17-VCAM1 in NSCLC-induced bone metastasis.