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

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.