Cathepsin K is a lysosomal cysteine proteinase primarily found in osteoclasts, where it plays a critical role in bone resorption and remodeling. Mutations in the cathepsin K gene cause pycnodysostosis, a rare inherited osteochondrodysplasia characterized by osteosclerosis, short stature, and acroosteolysis. To investigate the role of cathepsin K in bone resorption, researchers generated mice with a targeted disruption of the cathepsin K gene. These mice survived and were fertile but exhibited an osteopetrotic phenotype with excessive trabeculation of the bone-marrow space. Cathepsin-K-deficient osteoclasts showed altered ultrastructural features, including a poorly defined resorption surface, broad demineralized matrix fringe, and absence of collagen-fibril-containing vacuoles. In vitro assays revealed severely impaired resorptive activity, supporting the role of cathepsin K in bone remodeling. Skeletal remodeling involves both bone resorption and formation. Osteoclasts generate an acidic microenvironment for bone demineralization and matrix degradation. Active proteases, including cathepsin K, are involved in matrix degradation. Cathepsin K, a member of the papain-cysteine protease family, is highly expressed in human osteoclasts. Overexpressed baculovirus cathepsin K degrades bone-matrix proteins, including collagen and osteopontin, at low pH. Mutations in the cathepsin K gene are linked to pycnodysostosis, a hereditary bone disorder with defective osteoclast function. To investigate cathepsin K's role, researchers generated cathepsin-K-deficient mice by targeting the gene. These mice developed osteopetrosis, a condition characterized by excessive bone density and impaired resorption. Their osteoclasts exhibited altered morphology, suggesting a key role for cathepsin K in bone resorption. The mice may serve as a valuable model for pycnodysostosis. The study used various methods, including gene targeting, RT-PCR, Northern and Western blot analyses, radiographs, histology, and electron microscopy. Results showed that cathepsin-K-deficient mice had no cathepsin K RNA or protein, and their osteoclasts had impaired resorption activity. The mice exhibited an osteopetrotic phenotype with dense trabeculation of bone-marrow spaces, thickened trabeculae, and increased primary spongiosa in vertebrae. Histological examination confirmed these findings, showing unresorbed primary spongiosa in the metaphyses of 5-week-old mice. The study demonstrated that cathepsin K is essential for bone resorption, and its deficiency leads to osteopetrosis. The findings highlight the importance of cathepsCathepsin K is a lysosomal cysteine proteinase primarily found in osteoclasts, where it plays a critical role in bone resorption and remodeling. Mutations in the cathepsin K gene cause pycnodysostosis, a rare inherited osteochondrodysplasia characterized by osteosclerosis, short stature, and acroosteolysis. To investigate the role of cathepsin K in bone resorption, researchers generated mice with a targeted disruption of the cathepsin K gene. These mice survived and were fertile but exhibited an osteopetrotic phenotype with excessive trabeculation of the bone-marrow space. Cathepsin-K-deficient osteoclasts showed altered ultrastructural features, including a poorly defined resorption surface, broad demineralized matrix fringe, and absence of collagen-fibril-containing vacuoles. In vitro assays revealed severely impaired resorptive activity, supporting the role of cathepsin K in bone remodeling. Skeletal remodeling involves both bone resorption and formation. Osteoclasts generate an acidic microenvironment for bone demineralization and matrix degradation. Active proteases, including cathepsin K, are involved in matrix degradation. Cathepsin K, a member of the papain-cysteine protease family, is highly expressed in human osteoclasts. Overexpressed baculovirus cathepsin K degrades bone-matrix proteins, including collagen and osteopontin, at low pH. Mutations in the cathepsin K gene are linked to pycnodysostosis, a hereditary bone disorder with defective osteoclast function. To investigate cathepsin K's role, researchers generated cathepsin-K-deficient mice by targeting the gene. These mice developed osteopetrosis, a condition characterized by excessive bone density and impaired resorption. Their osteoclasts exhibited altered morphology, suggesting a key role for cathepsin K in bone resorption. The mice may serve as a valuable model for pycnodysostosis. The study used various methods, including gene targeting, RT-PCR, Northern and Western blot analyses, radiographs, histology, and electron microscopy. Results showed that cathepsin-K-deficient mice had no cathepsin K RNA or protein, and their osteoclasts had impaired resorption activity. The mice exhibited an osteopetrotic phenotype with dense trabeculation of bone-marrow spaces, thickened trabeculae, and increased primary spongiosa in vertebrae. Histological examination confirmed these findings, showing unresorbed primary spongiosa in the metaphyses of 5-week-old mice. The study demonstrated that cathepsin K is essential for bone resorption, and its deficiency leads to osteopetrosis. The findings highlight the importance of catheps