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Background— Cathepsin K (catK), a lysosomal cysteine protease, was identified in a gene-profiling experiment that compared human early plaques, advanced stable plaques, and advanced atherosclerotic plaques containing a thrombus, where it was highly upregulated in advanced stable plaques.

Methods and Results— To assess the function of catK in atherosclerosis, catK^−/−/apolipoprotein (apo) E^−/− mice were generated. At 26 weeks of age, plaque area in the catK^−/−/apoE^−/− mice was reduced (41.8%) owing to a decrease in the number of advanced lesions as well as a decrease in individual advanced plaque area. This suggests an important role for catK in atherosclerosis progression. Advanced plaques of catK^−/−/apoE^−/− mice showed an increase in collagen content. Medial elastin fibers were less prone to rupture than those of apoE^−/− mice. Although the relative macrophage content did not differ …