Inactivation of the osteopontin gene enhances vascular calcification of matrix Gla protein-deficient mice: evidence for osteopontin as an inducible inhibitor of vascular calcification in vivo.
Osteopontin (OPN) is abundantly expressed in human calcified arteries. To examine the role of OPN in vascular calcification, OPN mutant mice were crossed with matrix Gla protein (MGP) mutant mice. Mice deficient in MGP alone (MGP(-/-) OPN(+/+)) showed calcification of their arteries as early as 2 weeks (wk) after birth (0.33 +/- 0.01 mmol/g dry weight), and the expression of OPN in the calcified arteries was greatly up-regulated compared with MGP wild-types. OPN accumulated adjacent to the mineral and colocalized to surrounding cells in the calcified media. Cells synthesizing OPN lacked smooth muscle (SM) lineage markers, SM alpha-actin and SM22alpha. However, most of them were not macrophages. Importantly, mice deficient in both MGP and OPN had twice as much arterial calcification as MGP(-/-) OPN(+/+) at 2 wk, and over 3 times as much at 4 wk, suggesting an inhibitory effect of OPN in vascular calcification. Moreover, these mice died significantly earlier (4.4 +/- 0.2 wk) than MGP(-/-) OPN(+/+) counterparts (6.6 +/- 1.0 wk). The cause of death in these animals was found to be vascular rupture followed by hemorrhage, most likely due to enhanced calcification. These studies are the first to demonstrate a role for OPN as an inducible inhibitor of ectopic calcification in vivo.
Speer
Mei Y
MY
Bioengineering Department, University of Washington, Seattle 98195, USA.
McKee
Marc D
MD
Guldberg
Robert E
RE
Liaw
Lucy
L
Yang
Hsueh-Ying
HY
Tung
Elyse
E
Karsenty
Gerard
G
Giachelli
Cecilia M
CM
D000818:Animals; D001158:Arteries / Q000378:metabolism / Q000473:pathology*; D002114:Calcinosis / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D016326:Extracellular Matrix Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053495:Osteopontin; D012795:Sialoglycoproteins / Q000235:genetics* / Q000502:physiology; D000097568:Matrix Gla Protein
D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D053495:Osteopontin; D012795:Sialoglycoproteins; D000097568:Matrix Gla Protein; C506895:SPP1 protein, human; C506896:Spp1 protein, mouse