Cathepsin K Knockout Mice Develop Osteopetrosis Due to a Deficit in Matrix Degradation but Not Demineralization

Authors

  • Maxine Gowen,

    Corresponding author
    1. Department of Bone and Cartilage Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A.
    • Address reprint requests to: Maxine Gowen SmithKline Beecham Pharmaceuticals UW2109 709 Swedeland Road P.O. Box 1539 King of Prussia, PA 19406 U.S.A.
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  • Francesca Lazner,

    1. Molecular Genetics and Development Group, Institute of Reproduction and Development, Monash University, Monash Medical Centre, Clayton Victoria, Australia
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  • Robert Dodds,

    1. Department of Bone and Cartilage Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A.
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  • Rasesh Kapadia,

    1. Department of Bone and Cartilage Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A.
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  • John Feild,

    1. Department of Molecular Genetics, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A.
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  • Michael Tavaria,

    1. Molecular Genetics and Development Group, Institute of Reproduction and Development, Monash University, Monash Medical Centre, Clayton Victoria, Australia
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  • Ivan Bertoncello,

    1. Molecular Genetics and Development Group, Institute of Reproduction and Development, Monash University, Monash Medical Centre, Clayton Victoria, Australia
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  • Fred Drake,

    1. Department of Bone and Cartilage Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A.
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  • Silva Zavarselk,

    1. Molecular Genetics and Development Group, Institute of Reproduction and Development, Monash University, Monash Medical Centre, Clayton Victoria, Australia
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  • Irene Tellis,

    1. Molecular Genetics and Development Group, Institute of Reproduction and Development, Monash University, Monash Medical Centre, Clayton Victoria, Australia
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  • Paul Hertzog,

    1. Molecular Genetics and Development Group, Institute of Reproduction and Development, Monash University, Monash Medical Centre, Clayton Victoria, Australia
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  • Christine Debouck,

    1. Department of Molecular Genetics, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A.
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  • Ismail Kola

    1. Molecular Genetics and Development Group, Institute of Reproduction and Development, Monash University, Monash Medical Centre, Clayton Victoria, Australia
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Abstract

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.

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