Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. IL-6 is a multifunctional cytokine that is associated with the disease status and outcomes of cancers. However, the effect of IL-6 on the migration activity of human chondrosarcoma cells is mostly unknown. Here, we found that IL-6 increased the migration and expression of MMP-13 in human chondrosarcoma cells. We also found that human chondrosarcoma tissues had significant expression of IL-6, which was higher than that in normal cartilage. IL-6-mediated migration and MMP-13 up-regulation were attenuated by anti-IL-6 receptor antibody, Ras, Raf-1, and a MEK inhibitor. Activation of the Ras, Raf-1, MEK, ERK, and NF-B signaling pathways after IL-6 treatment was demonstrated, and IL-6-induced MMP-13 expression and migration activity were inhibited by the specific inhibitor and mutant Ras, Raf-1, MEK, ERK, and NF-B cascades. In addition, migration-prone sublines demonstrated that cells with increasing migration ability had greater expression of IL-6 and MMP-13. Taken together, these results indicate that IL-6 and IL-6 receptor interaction enhances migration of chondrosarcoma through an increase in MMP-13 production.Chondrosarcoma is the second most common malignancy of bone, and it has a poor response to the chemotherapy or radiation treatment currently used, making the management of chondrosarcomas a complicated challenge (1). Clinically, surgical resection remains the primary mode of therapy for chondrosarcoma. In the absence of an effective adjuvant therapy, this mesenchymal malignancy has a poor prognosis, and therefore, it is important to explore novel and adequate remedies (2). Because chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and metastasize distantly (2), an approach that decreases its ability to invade and metastasize may facilitate the development of effective adjuvant therapy.The tumor metastatic cascade consists of multiple successive steps, including adhesion of tumor cells at the primary site, invasion into the intravascular space, dissemination to distant sites, adhesion of tumor cells to the vascular endothelium of distant tissues, extravasation and invasion into surrounding tissues, and finally formation of secondary tumor colonies (3). To facilitate the cell motility, invading cells need to change the cell-cell adhesion properties, rearrange the extracellular matrix environment, suppress anoikis, and reorganize their cytoskeletons (4). Matrix metalloproteinases (MMPs) 3 have important roles in these processes because their proteolytic activities assist in degradation of the extracellular matrix and basement membrane (5, 6). MMPs, cytokines, growth factors, and chemokines have been shown to regulate tumor cell invasion through autocrine or paracrine pathways (4). Previous studies demonstrated the expression of MMP-1, -2, -3, -9, and MMP-13 in human chondrosarcoma cel...