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.

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. METHODS AND
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.