title: Atorvastatin-induced increase in progenitor cell levels is rather caused by enhanced receptor activator of NF-kappaB ligand (RANKL) cell proliferation than by bone marrow mobilization.
abstract: BACKGROUND
  Statins have been shown to increase the level of circulating progenitor cells in peripheral blood supposedly due to a mobilization of progenitor cells from the bone marrow niche. Osteoclast/osteoblast interaction has been associated with progenitor cell mobilization. Here, we investigated the role of statins on progenitor cell mobilization with a focus on bone metabolism.
  
  
  RESULTS
  FGF2(-/-) and wild type (wt) mice were treated with atorvastatin or placebo. In contrast to wt mice, the number of sca-1/flk-1 positive progenitor cells in peripheral blood (PB) of atorvastatin treated FGF2(-/-) mice did not increase, and was accompanied by a defective reendothelialization after perielectric injury of the common carotid artery. In wt, but not FGF2(-/-) mice, statin treatment was associated with increased levels of receptor activator of NF-κB ligand (RANKL) in bone marrow (BM) supernatant. Treatment with recombinant RANKL increased sca-1/flk-1 positive progenitors in FGF2(-/-) mice. Interestingly, osteoclast activation was not altered. To measure the egress of sca-1/flk-1 positive progenitor cells from the bone marrow, we performed in-situ perfusion experiments of isolated hind limbs. Mobilization was not significantly affected by atorvastatin in both wt and FGF2(-/-) mice. Furthermore, RANK - the specific receptor to RANKL - is expressed on progenitor cells, and RANKL stimulation increases cell proliferation in vitro and in vivo.
  
  
  CONCLUSIONS
  Atorvastatin treatment increases RANKL levels with no measurable effect on bone metabolism and mobilization of progenitor cells from BM to PB. RANKL is essential for the statin-mediated increase of progenitor cell levels but predominantly due to a RANKL-induced stimulation of cell proliferation.
authors.affiliation: Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Steinmetz
authors.forename: Bastian
authors.initials: B
authors.lastname: Pelster
authors.forename: Eva
authors.initials: E
authors.lastname: Lucanus
authors.forename: Jean Francois
authors.initials: JF
authors.lastname: Arnal
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
authors.forename: Nikos
authors.initials: N
authors.lastname: Werner
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D000069059:Atorvastatin; D001853:Bone Marrow / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology*; D006614:Hindlimb / Q000098:blood supply; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D053244:Osteoprotegerin / Q000378:metabolism; D010477:Perfusion; D011758:Pyrroles / Q000494:pharmacology*; D053245:RANK Ligand / Q000502:physiology*; D062326:Re-Epithelialization; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D053244:Osteoprotegerin; D011758:Pyrroles; D053245:RANK Ligand; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D016222:Fibroblast Growth Factor 2; D000069059:Atorvastatin; D040301:Vascular Endothelial Growth Factor Receptor-2