Abstract 5524: Progenitor Cell Mobilization is FGF-2 Dependant and Results in the Activation of Osteoclasts
Background Fibroblast growth factor-2 (FGF2) regulates proliferation of bone marrow (BM) stromal cells and has pro-angiogenic effects regulating endothelial cell growth, migration, and reendothelialization. Here we determine the underlying molecular mechanisms of FGF2-dependent statin-mediated progenitor cell mobilization.
Methods and Results To determine the molecular mechanisms of FGF2-mediated progenitor cell mobilization, FGF2−/− and wild type (wt) mice were treated with atorvastatin (10mg/kg body weight s.c. per day) and placebo. In contrast to wt mice, the number of Sca1/flk-1 positive EPC in peripheral blood (flow cytometry) of atorvastatin treated FGF2−/− mice did not increase. This was due to an accumulation of Sca1/flk-1 positive cells within the BM. Inhibition of EPC mobilization in FGF2−/− mice was associated with a delay in reendothelialization in a mouse model of a focal endothelial cell denudation and a severe reduction in neoangiogenesis despite statin treatment. BM transplantation experiments demonstrated that reconstitution of FGF2−/− mice with wt stem cells completely restored statin-mediated EPC mobilization while wt mice reconstituted with FGF2−/− stem cells developed a severe mobilization defect associated with an impaired endothelial dependent vasorelaxation (organ chamber) and enhanced neointima formation. In wt mice, statin treatment was associated with an increased number of activated osteoclasts compared to placebo treated mice which are known to play a pivotal role in stem cell mobilization. Treatment with osteoclast-activating RANKL induced an effective mobilization of Sca1/flk1 and Sca1/CD117 positive progenitor cells and enhanced the number of early outgrowth EPC.
Conclusion Medullary FGF2 is essential in the statin-mediated mobilization of EPC from BM into peripheral blood. A reduction in the number and activation status of osteoclasts may account for the impairment in EPC mobilization.