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

Abstract

Objective— 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) −/− 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 −/− OPG −/− mice with ApoE −/− OPG +/+ bone marrow (BM) would be sufficient to rescue lesion progression and vascular calcification. Conversely, reconstitution of ApoE −/− OPG +/+ mice with ApoE −/− OPG −/− BM may accelerate lesion progression and vascular calcification. Approach and Results— ApoE −/− OPG −/− mice transplanted with ApoE −/− OPG +/+ BM developed smaller atherosclerotic lesions and deposited less calcium in the innominate artery than that of ApoE −/− OPG −/− mice transplanted with ApoE −/− OPG −/− BM. There were no differences in lesion size and calcification in ApoE −/− OPG +/+ mice transplanted with BM from ApoE −/− OPG −/− or ApoE −/− OPG +/+ mice. The large lesions observed in the ApoE −/− OPG −/− mice transplanted with OPG −/− BM were rich in chondrocyte-like cells, collagen, and proteoglycans. Importantly, the ApoE −/− OPG −/− mice transplanted with OPG +/+ BM remained osteoporotic, and the ApoE −/− OPG +/+ 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 −/− OPG −/− BM induced more vascular smooth muscle cell calcification than cells derived from ApoE −/− OPG +/+ mice. Conclusions— 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.