G-CSF increases mesenchymal precursor cell numbers in the bone marrow via an indirect mechanism involving osteoclast-mediated bone resorption

During the course of studies to investigate whether MPC circulate in response to G-CSF, the agent most frequently used to induce mobilization of hematopoietic progenitors, we observed that while G-CSF failed to increase the number of MPC in circulation (assayed in vitro as fibroblast colony-forming cells, CFU-F), G-CSF administration nevertheless resulted in a time-dependent increase in the absolute number of CFU-F within the BM, peaking at Day 7. Treatment of BM cells from G-CSF-treated mice with hydroxyurea did not alter CFU-F numbers, suggesting that the increase in their numbers in response to G-CSF administration is not due to proliferation of existing CFU-F. Given previous studies demonstrating that G-CSF potently induces bone turnover in mice, we hypothesized that the increase in CFU-F may be triggered by the bone resorption that occurs following G-CSF administration. In accord with this hypothesis, administration of an inhibitor of osteoclast differentiation, osteoprotegerin (OPG), prevented the increase of CFU-F numbers induced by G-CSF. In conclusion, these data indicate that the cytokine treatment routinely used to mobilize hematopoietic stem cells could provide a readily applicable method to induce in vivo expansion of MPC for clinical applications.