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Atherosclerosis/Lipoproteins

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

A. Callegari, M. Coons, J.L. Ricks, H.L. Yang, T.S. Gross, P. Huber, M.E. Rosenfeld, M. Scatena
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https://doi.org/10.1161/ATVBAHA.113.301755
Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;ATVBAHA.113.301755
Originally published August 29, 2013
A. Callegari
From the Departments of Bioengineering (A.C., M.C., H.L.Y., M.S.), Pathology (J.L.R., M.E.R.), and Orthopaedics and Sports Medicine (T.S.G., P.H.), University of Washington, Seattle, WA.
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M. Coons
From the Departments of Bioengineering (A.C., M.C., H.L.Y., M.S.), Pathology (J.L.R., M.E.R.), and Orthopaedics and Sports Medicine (T.S.G., P.H.), University of Washington, Seattle, WA.
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J.L. Ricks
From the Departments of Bioengineering (A.C., M.C., H.L.Y., M.S.), Pathology (J.L.R., M.E.R.), and Orthopaedics and Sports Medicine (T.S.G., P.H.), University of Washington, Seattle, WA.
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H.L. Yang
From the Departments of Bioengineering (A.C., M.C., H.L.Y., M.S.), Pathology (J.L.R., M.E.R.), and Orthopaedics and Sports Medicine (T.S.G., P.H.), University of Washington, Seattle, WA.
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T.S. Gross
From the Departments of Bioengineering (A.C., M.C., H.L.Y., M.S.), Pathology (J.L.R., M.E.R.), and Orthopaedics and Sports Medicine (T.S.G., P.H.), University of Washington, Seattle, WA.
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P. Huber
From the Departments of Bioengineering (A.C., M.C., H.L.Y., M.S.), Pathology (J.L.R., M.E.R.), and Orthopaedics and Sports Medicine (T.S.G., P.H.), University of Washington, Seattle, WA.
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M.E. Rosenfeld
From the Departments of Bioengineering (A.C., M.C., H.L.Y., M.S.), Pathology (J.L.R., M.E.R.), and Orthopaedics and Sports Medicine (T.S.G., P.H.), University of Washington, Seattle, WA.
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M. Scatena
From the Departments of Bioengineering (A.C., M.C., H.L.Y., M.S.), Pathology (J.L.R., M.E.R.), and Orthopaedics and Sports Medicine (T.S.G., P.H.), University of Washington, Seattle, WA.
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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.

  • atherosclerosis
  • osteoprotegerin
  • vascular calcification
  • Received April 24, 2013.
  • Accepted August 20, 2013.
  • © 2013 American Heart Association, Inc.
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    Bone Marrow– or Vessel Wall–Derived Osteoprotegerin Is Sufficient to Reduce Atherosclerotic Lesion Size and Vascular Calcification
    A. Callegari, M. Coons, J.L. Ricks, H.L. Yang, T.S. Gross, P. Huber, M.E. Rosenfeld and M. Scatena
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;ATVBAHA.113.301755, originally published August 29, 2013
    https://doi.org/10.1161/ATVBAHA.113.301755

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    Bone Marrow– or Vessel Wall–Derived Osteoprotegerin Is Sufficient to Reduce Atherosclerotic Lesion Size and Vascular Calcification
    A. Callegari, M. Coons, J.L. Ricks, H.L. Yang, T.S. Gross, P. Huber, M.E. Rosenfeld and M. Scatena
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;ATVBAHA.113.301755, originally published August 29, 2013
    https://doi.org/10.1161/ATVBAHA.113.301755
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