Bone Marrow– or Vessel Wall–Derived Osteoprotegerin Is Sufficient to Reduce Atherosclerotic Lesion Size and Vascular Calcification

<jats:sec> <jats:title>Objective—</jats:title> <jats:p> Osteoprotegerin (OPG) is a decoy receptor for the osteoclast differentiation factor receptor activator of NF-κB ligand. OPG regulates bone homeostasis, and its inactivation in mice results in severe osteoporosis. OPG deficiency in apolipoprotein E (ApoE) <jats:sup>−/−</jats:sup> mice results in increased atherosclerotic lesion size and calcification. Furthermore, receptor activator of NF-κB ligand enhances macrophage-dependent smooth muscle cell calcification in vitro. Here, we hypothesized that reconstitution of ApoE <jats:sup>−/−</jats:sup> OPG <jats:sup>−/−</jats:sup> mice with ApoE <jats:sup>−/−</jats:sup> OPG <jats:sup>+/+</jats:sup> bone marrow (BM) would be sufficient to rescue lesion progression and vascular calcification. Conversely, reconstitution of ApoE <jats:sup>−/−</jats:sup> OPG <jats:sup>+/+</jats:sup> mice with ApoE <jats:sup>−/−</jats:sup> OPG <jats:sup>−/−</jats:sup> BM may accelerate lesion progression and vascular calcification. </jats:p> </jats:sec> <jats:sec> <jats:title>Approach and Results—</jats:title> <jats:p> ApoE <jats:sup>−/−</jats:sup> OPG <jats:sup>−/−</jats:sup> mice transplanted with ApoE <jats:sup>−/−</jats:sup> OPG <jats:sup>+/+</jats:sup> BM developed smaller atherosclerotic lesions and deposited less calcium in the innominate artery than that of ApoE <jats:sup>−/−</jats:sup> OPG <jats:sup>−/−</jats:sup> mice transplanted with ApoE <jats:sup>−/−</jats:sup> OPG <jats:sup>−/−</jats:sup> BM. There were no differences in lesion size and calcification in ApoE <jats:sup>−/−</jats:sup> OPG <jats:sup>+/+</jats:sup> mice transplanted with BM from ApoE <jats:sup>−/−</jats:sup> OPG <jats:sup>−/−</jats:sup> or ApoE <jats:sup>−/−</jats:sup> OPG <jats:sup>+/+</jats:sup> mice. The large lesions observed in the ApoE <jats:sup>−/−</jats:sup> OPG <jats:sup>−/−</jats:sup> mice transplanted with OPG <jats:sup>−/−</jats:sup> BM were rich in chondrocyte-like cells, collagen, and proteoglycans. Importantly, the ApoE <jats:sup>−/−</jats:sup> OPG <jats:sup>−/−</jats:sup> mice transplanted with OPG <jats:sup>+/+</jats:sup> BM remained osteoporotic, and the ApoE <jats:sup>−/−</jats:sup> OPG <jats:sup>+/+</jats:sup> mice did not show signs of bone loss regardless of the type of BM received. In coculture experiments, macrophages and mesenchymal stem cells derived from ApoE <jats:sup>−/−</jats:sup> OPG <jats:sup>−/−</jats:sup> BM induced more vascular smooth muscle cell calcification than cells derived from ApoE <jats:sup>−/−</jats:sup> OPG <jats:sup>+/+</jats:sup> mice. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>These results indicate that OPG derived either from the BM or from the vessel wall is sufficient to slow down lesion progression and vascular calcification independent of bone turnover.</jats:p> </jats:sec>