Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice

Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice

^*Zentrum Biochemie und Molekulare Zellbiologie, Abteilung Biochemie II, Universität Göttingen, Gosslerstrasse 12 d, 37073 Göttingen, Germany; ^‡Universität Bern, M.E. Müller-Institut für Biomechanik, Murtenstrasse 35, CH-3010 Bern, Switzerland; ^§Department of Anatomy and Developmental Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom; ^¶Institut für Biochemie, Universität Jena, Löbder Strasse 3, 07740 Jena, Germany; and ^‖Zentrum Radiologie, Universität Göttingen, Robert-Koch-Strasse, 37073 Göttingen, Germany

Edited by Elizabeth F. Neufeld, University of California, Los Angeles, School of Medicine, Los Angeles, CA, and approved September 5, 1998 (received for review June 23, 1998)

Abstract

Cathepsin K is a recently identified lysosomal cysteine proteinase. It is abundant in osteoclasts, where it is believed to play a vital role in the resorption and remodeling of bone. Pycnodysostosis is a rare inherited osteochondrodysplasia that is caused by mutations of the cathepsin-K gene, characterized by osteosclerosis, short stature, and acroosteolysis of the distal phalanges. With a view to delineating the role of cathepsin K in bone resorption, we generated mice with a targeted disruption of this proteinase. Cathepsin-K-deficient mice survive and are fertile, but display an osteopetrotic phenotype with excessive trabeculation of the bone-marrow space. Cathepsin-K-deficient osteoclasts manifested a modified ultrastructural appearance: their resorptive surface was poorly defined with a broad demineralized matrix fringe containing undigested fine collagen fibrils; their ruffled borders lacked crystal-like inclusions, and they were devoid of collagen-fibril-containing cytoplasmic vacuoles. Assaying the resorptive activity of cathepsin-K-deficient osteoclasts in vitro revealed this function to be severely impaired, which supports the contention that cathepsin K is of major importance in bone remodeling.

Footnotes

↵ † To whom reprint requests should be addressed. e-mail: saftig{at}uni-bc2.gwdg.de.
This paper was submitted directly (Track II) to the Proceedings Office.
ABBREVIATIONS:

RT-PCR,

reverse transcription–PCR;

SEM,

scanning electron microscopy