Bone destruction by invading oral squamous carcinoma cells mediated by the transforming growth factor-β signalling pathway

Background: Gingival squamous cell carcinoma (SCC) cells frequently invade mandibular bone, and this destruction is associated with a worse prognosis. However, the relationship between bone destruction and associated factors is unclear. In this study, the role and diagnostic utility of transforming growth factor-β (TGF-β) type I receptor (TβRI) in bone destruction of the mandible was investigated. Patients and Methods: The expression of TβRI was explored by using an immunohistochemical method on paraffin-embedded tissues from 21 cases of mandibular SCC. An inhibitor of the kinase activity of the TβRI (TβRI-I) was used to assess the role of TβRI in bone destruction by a human oral SCC cell line (HSC-2) that highly expresses TβRI. Results: TβRI-positive signals were closely associated with destructive invasion of the mandible by oral SCC cells. Consistent with these results, TβRI-I greatly reduced HSC-2 cell-induced bone destruction and osteoclast formation in vivo and in vitro. TβRI-I treatment reduced the expression of TNF-α, RANKL and connective tissue growth factor (CTGF/CCN2), all of which were up-regulated by TGF-β in HSC-2 cells. Conclusion: These data demonstrated an important role for TGF-β signalling in bone invasion by oral SCC cells, and suggest that the bone destruction is mediated by RANKL, TNF-α and CCN2.