Bortezomib Induces Proliferation of Mesenchymal Progenitor Cells and Promotes Differentiation towards Osteoblastic Lineage

Bortezomib is a first-in-class proteasome inhibitor approved for the therapy of relapsed, refractory multiple myeloma (MM). Two large registration trials (SUMMIT and APEX) of bortezomib in MM revealed an increase in the serum levels of bone-specific alkaline phosphatase (b-ALP) and osteocalcin (ocn) in bortezomib-responsive patients, raising the prospect that bortezomib may influence the bone marrow (BM) microenvironment in association with its anti-myeloma effect,. However, the precise cellular target of bortezomib within the BM milieu remains unknown. We hypothesized that the observed rise in b-ALP and ocn was the result of direct effects of bortezomib on osteoblast-lineage committed cells. The effect of bortezomib on osteoblastic cells was first evaluated in in vitro. When bortezomib was added to freshly isolated primary BM mononuclear cells, the CFU-Ob (osteoblastic colony-forming units) was unchanged, but the colony size was increased, with a maximum effect observed at 1 nM. In particular, bortezomib increased the number of CD45−/CD51+ cells 1.8 fold (P