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, individual macrophage size increased. In vitro studies of bone marrow derived–macrophages confirmed this observation. Scavenger receptor–mediated uptake (particularly by CD36) of modified LDL increased in the absence of catK, resulting in an increased macrophage size because of increased cellular storage of cholesterol esters, thereby enlarging the lysosomes.

Conclusions— A deficiency of catK reduces plaque progression and induces plaque fibrosis but aggravates macrophage foam cell formation in atherosclerosis.