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.
- Received April 24, 2013.
- Accepted August 20, 2013.
- © 2013 American Heart Association, Inc.