The study investigates the role of cathepsin K in bone resorption by generating mice with a targeted disruption of the cathepsin-K gene. These mice, known as cathepsin-K-deficient mice, survive and are fertile but exhibit an osteopetrotic phenotype characterized by excessive trabeculation of the bone-marrow space. Ultrastructural analysis of osteoclasts from these mice reveals a modified appearance, with a poorly defined resorptive surface, a broad demineralized matrix fringe containing undigested fine collagen fibrils, and a lack of crystal-like inclusions in the ruffled borders. In vitro assays show severely impaired resorptive activity in cathepsin-K-deficient osteoclasts, supporting the importance of cathepsin K in bone remodeling. The findings suggest that cathepsin K is crucial for maintaining normal bone resorption and that cathepsin-K-deficient mice may serve as a valuable model for pycnodystosis, a rare inherited osteochondrodysplasia characterized by osteosclerosis, short stature, and acroosteolysis.The study investigates the role of cathepsin K in bone resorption by generating mice with a targeted disruption of the cathepsin-K gene. These mice, known as cathepsin-K-deficient mice, survive and are fertile but exhibit an osteopetrotic phenotype characterized by excessive trabeculation of the bone-marrow space. Ultrastructural analysis of osteoclasts from these mice reveals a modified appearance, with a poorly defined resorptive surface, a broad demineralized matrix fringe containing undigested fine collagen fibrils, and a lack of crystal-like inclusions in the ruffled borders. In vitro assays show severely impaired resorptive activity in cathepsin-K-deficient osteoclasts, supporting the importance of cathepsin K in bone remodeling. The findings suggest that cathepsin K is crucial for maintaining normal bone resorption and that cathepsin-K-deficient mice may serve as a valuable model for pycnodystosis, a rare inherited osteochondrodysplasia characterized by osteosclerosis, short stature, and acroosteolysis.