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.

Shift of Macrophage Phenotype Due to Cartilage Oligomeric Matrix Protein Deficiency Drives Atherosclerotic Calcification

“…Knockout of osteoprotegerin, the inhibitor of receptor activator of nuclear factor-κB ligand-dependent osteoclast formation, leads to reduced lesion calcification. 37,38 Similarly, VSMC-specific knockout of Runx2 reduced the level of receptor activator of nuclear factor-κB ligand and subsequent osteoclast differentiation of macrophages and thereby inhibited atherosclerotic calcification.…”

Osteoprotegerin is independently associated with metabolic syndrome and microvascular complications in type 2 diabetes mellitus

“…11 Vessel wall-derived OPG was able to inhibit calcium deposition in ApoE−/− OPG−/− knockout animal models, indicating the ability of endogenous OPG to inhibit vascular calcification, further suggesting that systemic elevation of OPG may be an adaptive response factor. 12 Taken together, it remains unclear whether targeting RANK-RANKL may have a role in modifying vascular disease.…”

Vascular Function

“…The adhesion and migration of inflammatory cells produce an oxidizing environment, which is critical for the progression of vascular diseases. 27 demonstrated that osteoprotegerin derived from the bone marrow block the progression of vascular calcification. 27 About the pathogenesis of aneurysms, Marinkovic et al 28 performed an interesting study to limit aneurysm growth by inhibition of inflammation and reducing EC activation with immunosuppressive drug azathioprine.…”

“…27 demonstrated that osteoprotegerin derived from the bone marrow block the progression of vascular calcification. 27 About the pathogenesis of aneurysms, Marinkovic et al 28 performed an interesting study to limit aneurysm growth by inhibition of inflammation and reducing EC activation with immunosuppressive drug azathioprine. They showed that azathioprine has an anti-inflammatory effect in ECs and inhibits Rac1 and c-Jun-terminal-N-kinase activation, which may explain its protective role in the development of aneurysm formation and severity.…”