Bone microstructural and biomechanical properties were analyzed in mice genetically lacking cathepsin K (CatK). CatK deficiency (CatK^−/−) produced mild osteopetrosis, elevated numbers of osteoclasts, regions of disorganized bone microstructure, and increased bone fragility, showing how chronic alteration of enzyme activity during skeletal development dramatically affects bone organization and function.

Introduction: Mouse models of CatK deficiency recapitulate the osteopetrosis of human pyknodysostosis and allow study of clinically relevant issues: how inhibition of this enzyme activity affects bone integrity structurally and biomechanically. To address these questions, we generated CatK‐deficient mice by targeted disruption of the Ctsk gene and compared their bone structural and mechanical properties with wildtype (WT) controls.

Materials and Methods: Standard histomorphometric and biomechanical analyses were performed on femora from C57BL/6J male and female CatK^−/−, CatK^+/−, and WT mice.

Results: CatK^−/− femora exhibited the mild metaphyseal osteopetrosis, a greater cortical bone area and thickness, normal bone strength, but a high degree of brittleness (nearly 50–70% decrease in postyield displacement versus WT) and a 30–40% reduction in the work‐to‐failure. In cancellous bone, osteoclast numbers and resorption surface were increased markedly (∼150% and 50%, respectively), despite the overall decrease in net bone resorption for CatK‐deficient mice. Bone formation indices were altered in CatK^−/− mice as well, with significant increases in mineral appositional rate, but not in bone formation surface; these data suggest difference in osteoblast work but not in their recruitment in CatK deficiency. CatK‐deficient cortical bones had large areas of woven bone and intracortical resorption spaces within the disorganized tissue. Bone phenotype in CatK^−/− was similar in males and females.

Conclusions: Genetic CatK deficiency in mice results not only in the impairment of osteoclast function and osteopetrosis, but also altered osteoblast function, defective tissue organization, and very brittle bones. Whether this bone fragility in CatK deficiency results entirely from indirect effects of suppressed bone turnover because of impaired osteoclast function or perhaps represents a previously unappreciated more direct role for CatK in bone formation remains to be established.