Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrixdegradation but not demineralization

Cathepsin K is a cysteine protease expressed predominantly in osteoclasts, Activated cathepsin K cleaves key bone matrix proteins and is believed to p lay an important role in degrading the organic phase of bone during bone re sorption, Mutations in the human cathepsin K gene have been demonstrated to be associated with a rare skeletal dysplasia, pycnodysostosis. The degree of functional activity of the mutated forms of cathepsin K in these individ uals has not been elucidated, but is predicted to be low or absent, To stud y the role of cathepsin K in bone resorption, we have generated mice defici ent in the cathepsin K gene, Histologic and radiographic analysis of the mi ce revealed osteopetrosis of the long bones and vertebrae, and abnormal joi nt morphology, X-ray microcomputerized tomography images allowed quantitati on of the increase in bone volume, trabecular thickness, and trabecular num ber in both the primary spongiosa and the metaphysis of the proximal tibiae , Not all bones were similarly affected. Chondrocyte differentiation was no rmal. The mice also had abnormalities in hematopoietic compartments, partic ularly decreased bone marrow cellularity and splenomegaly, The heterozygous animals appeared normal. Close histologic examination of bone histology re vealed fully differentiated osteoclasts apposed to small regions of deminer alized bone. This strongly suggests that cathepsin K-deficient osteoclasts are capable of demineralizing the extracellular matrix but are unable to ad equately remove the demineralized bone. This is entirely consistent,vith th e proposed function of cathepsin K as a matrix-degrading proteinase in bone resorption.