Mechanism of Action of Bortezomib and the New Proteasome Inhibitors on Myeloma Cells and the Bone Microenvironment: Impact on Myeloma-Induced Alterations of Bone Remodeling

Figure 2

Effects of PIs on osteoblast and osteoclast remodeling in MM. PIs directly act on myeloma cells and on MM-induced alterations of bone remodeling. PIs block osteoclast formation from monocyte and the effects of RANKL on osteoclastogenesis. A direct effect of PIs on mature osteoclast has been shown. PIs stimulate osteogenic differentiation of BMSCs and osteoblast progenitors increasing osteoblast number and function. A stimulatory effect of PIs on the osteogenic transcription factor Runx2 has been demonstrated. PIs reduce Dkk-1 production and consequently affect β-catenin. PIs stimulate osteocyte viability and blunt the effect of glucocorticoid on osteocytes. PIs: proteasome inhibitors; RANKL: receptor activator of nuclear factor kappa B (NF-κB) ligand; BMSC: bone marrow stromal cell; Pre-OB: osteoblast progenitor.