Vascular calcification is now recognized as a widespread, clinically significant process similar to bone formation. Paradoxically, it correlates with osteoporosis. Both are linked to atherosclerosis and hyperlipidemia. We have recently provided evidence that oxidized lipids regulate mineralization, promoting matrix calcification by vascular cells and blocking matrix calcification by bone cells in vitro. We further showed that hyperlipidemia is associated with significantly reduced bone mineral density and content in mice. Bone mineral density in vivo is regulated not only by osteoblastic activity, but also by resorptive activity of osteoclasts. and effects of oxidized lipids and hyperlipidernia on osteoclastic differentiation and function are not known. In osteoporosis, osteoclastic activity overtakes osteoblastic activity. We now hypothesize that oxidized lipids regulate differentiation and function of mineral-resorbing osteoclastic cells in bone and artery wall. These regulatory effects of lipids on osteoclastic differentiation could also be dependent on factors produced by stromal cells in the two tissues. Specifically, we hypothesize (1) that osteoclast-like cells are present in artery wall as well as in bone and are regulated by oxidized lipids in both tissues, (2) that oxidized lipids regulate stromal cell production of and response to osteoclastogenic factors such as M-CSF, RANKL, PTH, and IL-6, and (3) that the atheroprotective enzyme paraoxonase also prevents both hyperlipidemia-induced vascular calcification and bone loss in vivo. To test these specific hypotheses we will: 1) examine human and mouse arterial specimens for osteoclastic markers and activity and test whether oxidized lipids affect osteoclastogenesis using in vitro models of vascular and bone tissue, 2) assess stromal cell production of M-CSF, IL-6 and RANKL before and after treatment with oxidized lipids and test stromal cell responsiveness to osteolytic stimuli, PTH and IL-6 in vitro and in vivo. and 3) determine whether deactivation of oxidized lipids by paraoxonase blocks oxidized lipid and hyperlipidemla- induced vascular calcification and bone loss in vitro and in vivo. Elucidating the mechanism by which oxidized lipids regulate mineral resorption will allow novel treatment approaches for osteoporosis and vascular calcification, including the possibility of biologically controlled regression of vascular calcification.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL069261-04
Application #
6796774
Study Section
Special Emphasis Panel (ZHL1-CSR-O (S1))
Program Officer
Applebaum-Bowden, Deborah
Project Start
2001-09-30
Project End
2005-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
4
Fiscal Year
2004
Total Cost
$381,250
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Garfinkel, Alan; Tintut, Yin; Petrasek, Danny et al. (2004) Pattern formation by vascular mesenchymal cells. Proc Natl Acad Sci U S A 101:9247-50
Tintut, Yin; Morony, Sean; Demer, Linda L (2004) Hyperlipidemia promotes osteoclastic potential of bone marrow cells ex vivo. Arterioscler Thromb Vasc Biol 24:e6-10
Abedin, Moeen; Tintut, Yin; Demer, Linda L (2004) Mesenchymal stem cells and the artery wall. Circ Res 95:671-6

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