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

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journal contribution
posted on 1999-10-01, 00:00 authored by M Gowen, F Lazner, R Dodds, R Kapadia, J Feild, M Tavaria, I Bertoncello, F Drake, Silva ZavarsekSilva Zavarsek, I Tellis, P Hertzog, C Debouck, I Kola
Cathepsin K is a cysteine protease expressed predominantly in osteoclasts. Activated cathepsin K cleaves key bone matrix proteins and is believed to play an important role in degrading the organic phase of bone during bone resorption. 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 individuals has not been elucidated, but is predicted to be low or absent. To study the role of cathepsin K in bone resorption, we have generated mice deficient in the cathepsin K gene. Histologic and radiographic analysis of the mice revealed osteopetrosis of the long bones and vertebrae, and abnormal joint morphology. X-ray microcomputerized tomography images allowed quantitation of the increase in bone volume, trabecular thickness, and trabecular number in both the primary spongiosa and the metaphysis of the proximal tibiae. Not all bones were similarly affected. Chondrocyte differentiation was normal. The mice also had abnormalities in hematopoietic compartments, particularly decreased bone marrow cellularity and splenomegaly. The heterozygous animals appeared normal. Close histologic examination of bone histology revealed fully differentiated osteoclasts apposed to small regions of demineralized bone. This strongly suggests that cathepsin K-deficient osteoclasts are capable of demineralizing the extracellular matrix but are unable to adequately remove the demineralized bone. This is entirely consistent with the proposed function of cathepsin K as a matrix-degrading proteinase in bone resorption.

History

Journal

Journal of bone and mineral research

Volume

14

Issue

10

Pagination

1654 - 1663

Publisher

John Wiley & Sons

Location

Chichester, Eng.

ISSN

0884-0431

Language

eng

Publication classification

C1.1 Refereed article in a scholarly journal

Copyright notice

1999, American Society for Bone and Mineral Research