Leukocyte Cathepsin K Influences Atherosclerotic Lesion Composition and Bone Mineral Density in LDL-Receptor Deficient Mice

Cathepsin K (Cat K), an established drug target for osteoporosis, has recently been reported to be present in atherosclerotic lesions. Due to its proteolytic activity Cat K may influence the atherosclerotic lesion composition and stability. To assess the biological role of leukocyte Cat K, we used the technique of bone marrow transplantation to selectively disrupt Cat K in the hematopoietic system. Total bone marrow progenitor cells from Cat K +/+ , Cat K +/and Cat K -/mice were transplanted into X-ray irradiated LDL receptor knockout (LDLR -/) mice. The selective silencing of leukocyte Cat K resulted in phenotypic changes in bone formation with an increased total bone mineral density in the Cat K -/LDLR -/mice and an effect of gene dosage. In relation to atherogenesis, absence of leukocyte Cat K resulted in dramatically decreased collagen and modestly increased macrophage content of the atherosclerotic lesions but no difference as to lesion size was observed. Further characterization of the atherosclerotic lesions revealed less elastic lamina fragmentation and a significant increase of apoptotic and necrotic area in Cat K -/-