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

Abstract

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.

The effect of intra‐articular injection of autologous bone marrow stem cells on pain and knee function in patients with osteoarthritis

“…19 Furthermore, in the present study G-CSF was used for stimulation in vivo because there is an age-dependent factor which has influence in the decrease in the number of progenitor cells in BM in elderly patients 20 and G-CSF increases the number of hematopoietic stem cells in BM. 21,22 The safe use of G-CSF in healthy donors has been studied, with minor side effects such as headache, bone pain, weakness and nausea, which are generally transient and well tolerated. 23 Regarding the control group we used paracetamol since it was considered as the first line treatment, relieving pain and improving physical functioning with low long-term toxicity.…”

The Brain-Bone-Blood Triad: Traffic Lights for Stem-Cell Homing and Mobilization

“…17 G-CSF administration activates osteoclasts, which were recently shown to be involved in mediating the increased proliferation of bone marrow stromal progenitors. 27 These observations suggest that osteoclasts participate not only in bone resorption and HSPC mobilization, but also in the regulation of the bone marrow-supporting niches. Similarly, mice lacking CD45 have a distorted morphology and a reduction in osteoclast activity, resulting in mild osteopetrosis.…”

Potential Use of CXCR4 Antagonists to Mobilize Endothelial and Mesenchymal Stem Cells

“…A number of groups have investigated whether MSCs are mobilized from the bone marrow by G-CSF treatment, in both mouse models and man; however, the results have been negative [ 53,75,76 ] . Further studies in mice confi rmed that G-CSF does not stimulate MSC mobilization, but showed that G-CSF stimulated the proliferation of MSCs in the bone marrow through its ability to promote osteoclast resorption [ 53,77 ] .…”