The Journal of Experimental Medicine
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Published online 14 October 2002 doi:10.1084/jem.20020911
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© Rockefeller University Press, 0022-1007/2002/10/1047 $5.00
The Journal of Experimental Medicine, Volume 196, Number 8, 1047-1055

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



Mei Y. Speer1, Marc D. McKee2, Robert E. Guldberg3, Lucy Liaw4, Hsueh-Ying Yang1, Elyse Tung1, Gerard Karsenty5 and Cecilia M. Giachelli1

1 Bioengineering Department, University of Washington, Seattle, WA 98195
2 Department of Anatomy and Cell Biology, Faculty of Dentistry, McGill University, Montreal, Quebec, Canada H3A 2T5
3 School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332
4 Maine Medical Center Research Institute, Scarborough, ME 04074
5 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030

Address correspondence to Cecilia M. Giachelli, Bioengineering Department, Box 351720, Bagley Hall, University of Washington, Seattle, WA 98195. Phone: 206-543-0205; Fax: 206-616-9763; E-mail: Ceci{at}u.washington.edu

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 SM22{alpha}. 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.

Key Words: biomineralization • gene knockout • phenotype transition • smooth muscle cells • vessel rupture


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