Characterization of the Molecular Mechanism of the Bone-Anabolic Activity of Carfilzomib in Multiple Myeloma

摘要: Carfilzomib, the next generation of proteasome inhibitor, may increase osteoblast-related markers in patients with multiple myeloma, but molecular mechanism its effect on mesenchymal stem cell differentiation to osteoblasts remains unknown. Herein, we demonstrated that carfilzomib significantly promoted into osteoblasts. In osteoprogenitor cells and primary from induced increases alkaline phosphatase activity, matrix mineralization, calcium deposition via Wnt-independent activation β-catenin/TCF signaling. Using affinity pull-down assays immunoblotting analysis immunofluorescence, found stabilization both free active forms β-catenin a time- dose-dependent manner was not associated transcriptional regulation. Nuclear translocation protein TCF activity independent effects GSK3β-activation signaling by 19 Wnt ligands, 10 Frizzled receptors, LRP5/6 co-receptors. Blocking dominant negative TCF1 or TCF4 attenuated carfilzomib-induced mineralization. Thus, osteoblast pathway. These results provide novel critical understanding anabolic role myeloma-induced bone disease.