Imatinib Promotes Osteoblast Differentiation by Inhibiting PDGFR Signaling and Inhibits Osteoclastogenesis by Both Direct and Stromal Cell-Dependent Mechanisms

Abstract

Several lines of evidence suggest that imatinib may affect skeletal tissue. We show that inhibition by imatinib of PDGFR signaling in osteoblasts activates osteoblast differentiation and inhibits osteoblast proliferation and that imatinib inhibits osteoclastogenesis by both stromal cell-dependent and direct effects on osteoclast precursors. Introduction: Imatinib mesylate, an orally active inhibitor of the c-abl, c-kit, and platelet-derived growth factor receptor (PDGFR) tyrosine kinases, is in clinical use for the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal cell tumors. Interruption of both c-kit and c-abl signaling in mice induces osteopenia, suggesting that imatinib might have adverse effects on the skeleton. However, biochemical markers of bone formation increase in patients with CML starting imatinib therapy, whereas bone resorption is unchanged, despite secondary hyperparathyroidism. We assessed the actions of imatinib on bone cells in vitro to study the cellular and molecular mechanism(s) underlying the skeletal effects we observed in imatinib-treated patients. Materials and Methods: Osteoblast differentiation was assessed using a mineralization assay, proliferation by [

The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo

“…(39) In cultures of human stromal cells isolated from bone biopsies, treatment with imatinib significantly increased mineral deposi- tion (17,21) and decreased proliferation of stromal cells. (17,18) Similarly, imatinib increased mineralization (19) and partially inhibited proliferation (19,20) in primary rat stromal cells and murine cell lines. The proliferation, differentiation, and maturation of OBs are influenced by signaling pathways, including PDGFR, that are inhibited by dasatinib.…”

“…(17)(18)(19)(20) To determine whether OBs are similarly sensitive to dasatinib, we examined the effect of dasatinib on cell proliferation and mineral formation in rodent stromal cell cultures in vitro.…”

“…(13)(14)(15)(16) Studies from our laboratory (17) and those of others (18)(19)(20)(21) have shown that imatinib activates OB activity while inhibiting cell proliferation at least in part through the inhibition of PDGFR. In cultures of human and murine stromal cells and cell lines, treatment with therapeutically achievable concentrations of imatinib significantly increased mineral deposition (17,19,21) and decreased cell proliferation. (17)(18)(19)(20) In addition, imatinib treatment prevented the inhibitory effects of PDGF on mineralized matrix formation in vitro.…”

“…(17)(18)(19)(20) In addition, imatinib treatment prevented the inhibitory effects of PDGF on mineralized matrix formation in vitro. (17,19) These results suggest that tyrosine kinase inhibitors could inhibit OB proliferation and activate their differentiation in vitro. However, it remains to be seen whether dasatinib has any effects on OB activity.…”

“…In cultures of human and murine stromal cells and cell lines, treatment with therapeutically achievable concentrations of imatinib significantly increased mineral deposition (17,19,21) and decreased cell proliferation. (17)(18)(19)(20) In addition, imatinib treatment prevented the inhibitory effects of PDGF on mineralized matrix formation in vitro. (17,19) These results suggest that tyrosine kinase inhibitors could inhibit OB proliferation and activate their differentiation in vitro.…”