Bortezomib induces osteoblast differentiation via Wnt-independent activation of beta-catenin/TCF signaling

Inhibition of Wnt/beta-catenin/T-cell factor (TCF) signaling induces proliferation of mesenchymal stem cells and/or suppresses their differentiation into osteoblasts (OBs). Osteolysis in multiple myeloma (MM) is related to the suppression of canonical Wnt signaling caused by DKK1, a soluble inhibitor of this pathway secreted by MM cells. Bortezomib (Bzb) can induce OB differentiation in vitro and in vivo and its anti-MM efficacy linked to bone anabolic effects. However, the molecular basis of the action of Bzb on bone is not completely understood. In the present study, we show that Bzb promotes matrix mineralization and calcium deposition by osteoprogenitor cells and primary mesenchymal stem cells via Wnt-independent activation of beta-catenin/TCF signaling. Using affinity pull-down assays with immunoblotting and immunofluorescence, we found that Bzb induced stabilization of beta-catenin. Nuclear translocation of stabilized beta-catenin was associated with beta-catenin/TCF transcriptional activity that was independent of the effects of Wnt ligand-receptor-induced signaling or GSK3beta activation. Blocking the activation of beta-catenin/TCF signaling by dominant negative TCF attenuated Bzb-induced matrix mineralization. These results provide evidence that Bzb induces OB differentiation via Wnt-independent activation of beta-catenin/TCF pathway and suggest that proteasome inhibition therapy in MM may function in part by subverting tumor-induced suppression of canonical Wnt signaling in the bone microenvironment.