Bortezomib Inhibits Giant Cell Tumor of Bone through Induction of Cell Apoptosis and Inhibition of osteoclast Recruitment, Giant Cell Formation and Bone Resorption

Giant cell tumor of bone (GCTB) is a rare and highly osteolytic bone tumor usually leads to an extensive bone lesion. The purpose for this study was to discover novel therapeutic targets and identify potential agents for treating GCTB. After screening the serum cytokine profiles in 52 GCTB patients and 10 normal individuals using the ELISA assay, we found that NF-B signaling-related cytokines including TNF-α, MCP-1, IL-1α, and IL-17A were significantly increased in GCTB patients. The results were confirmed by immunohistochemistry that the expression and activity of p65 were significantly increased in GCTB patients. Moreover, all of the NF-B inhibitors tested suppressed GCTB cell growth, and Bortezomib (BZB), the well-known proteasome inhibitor, was the most potent inhibitor in blocking GCTB cells growth. Our results showed that BZB not only induced GCTB neoplastic stromal cells (NSCs) apoptosis, but also suppressed GCTB NSCs-induced giant cell differentiation, formation and resorption. Moreover, BZB specifically suppressed GCTB NSCs-induced pre-osteoclast recruitment. Furthermore, BZB ameliorated GCTB cells induced bone destruction in vivo. As a result, BZB suppressed NF-B-regulated gene expression in GCTB NSCs apoptosis, monocyte migration, angiogenesis and osteoclastogenesis. Particularly, the inhibitory effects of BZB were much better than the zoledronic acid, (ZA), a drug currently used in treating GCTB, in our in vitro experimental paradigms. Together, our results demonstrated that NF-B signaling pathway is highly activated in GCTB and BZB could suppress GCTB and osteolysis in vivo and in vitro, indicating that BZB is a potential agent in the treatment of GCTB.

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