Objective— Osteopontin (OPN), a noncollagenous adhesive protein, is implicated in atherosclerosis, in which macrophages within atherosclerotic plaques express OPN. However, it is not known whether the elevated OPN expression is a cause or result of atherosclerosis.

Methods and Results— We generated mice that lacked OPN and crossed them with apolipoprotein (apo) E–deficient mice and analyzed these mice with a mixed C57BL/6×129 background after 36 weeks on a normal chow diet. In female mice, OP^+/−E^−/− and OP^−/−E^−/− mice had significantly smaller atherosclerotic and inflammatory lesions compared with OP^+/+E^−/− mice, and that was reflected by smaller area of MOMA-2–positive staining. In male mice, however, there was no significant difference in the atherosclerosis lesion areas among 3 genotypes. In both OP^−/−E^−/− and OP^+/+E^−/− mice, typical atherosclerotic lesions were detected, which include necrotic core, foamy cell collections, and cholesterol clefts. However, we found that vascular mineral-deposited areas in 60-week-old male OP^−/−E^−/− mice were significantly increased compared with those in OP^+/+E^−/− male mice.

Conclusions— These results suggest that OPN plays a promoting effect in atherosclerosis and inhibitory effect in vascular calcification. The suppression of OPN expression in females should be considered a therapeutic possibility in atherosclerosis.