Bone invasion is a critical prognostic factor for patients with oral squamous cell carcinoma (OSCC). We established an orthotropic implantation model using the murine OSCC cell line, SCCVII, showing direct invasion of the mandible by OSCC. Using this model, we examined the molecular mechanisms of bone invasion and the role of parathyroid-related protein (PTHrP). We established PTHrP, stable, knock-down SCCVII cells. Knock-down of PTHrP caused decreased osteoclast formation in vitro relative to expression levels of PTHrP. In vivo models showed dramatic suppression of bone invasion in PTHrP knock-down cells, and the degree of suppression was more pronounced than the level of PTHrP knock-down. We looked at an additive role of transforming growth factor-β (TGF-β) in PTHrP-mediated bone invasion. TGF-β induced mRNA expression of PTHrP, showed no inhibitory effect on SCCVII cell proliferation, and caused epithelial mesenchymal trans-differentiation such as changes in the cells. Sections of resected mandibles from patients with invasive OSCC showed a great number of osteoclasts at bone invasion sites, strong expression of PTHrP, and decreased expression of E-cadherin in the tumour cells. Cancer-derived PTHrP appears to play a critical role in bone invasion by OSCC, mediated by osteoclasts. Moreover, TGF-β appears to act synergistically to accelerate mandibular bone invasion.