Calcified Tissue International

, Volume 73, Issue 4, pp 380–386

Cathepsin K Deficiency in Pycnodysostosis Results in Accumulation of Non-Digested Phagocytosed Collagen in Fibroblasts

Authors

    • Department of Cell Biology and HistologyAcademic Medical Centre, University of Amsterdam, 1100 DE Amsterdam
    • Department of PeriodontologyAcademic Centre for Dentistry, University of Amsterdam, Amsterdam
  • W. S. Hou
    • Department of Human GeneticsMount Sinai School of Medicine, New York, NY
  • X. Rialland
    • Department of PaediatricsCentre Hospitalier Universitaire d’Angers
  • W. Tigchelaar
    • Department of Cell Biology and HistologyAcademic Medical Centre, University of Amsterdam, 1100 DE Amsterdam
  • P. Saftig
    • Biochemical InstituteChristian-Albrechts University, Kiel
  • D. Brömme
    • Department of Human GeneticsMount Sinai School of Medicine, New York, NY
  • B. D. Gelb
    • Department of Human GeneticsMount Sinai School of Medicine, New York, NY
    • Department of PediatricsMount Sinai School of Medicine, New York, NY
  • W. Beertsen
    • Department of PeriodontologyAcademic Centre for Dentistry, University of Amsterdam, Amsterdam
Laboratory Investigation

DOI: 10.1007/s00223-002-2092-4

Cite this article as:
Everts, V., Hou, W., Rialland, X. et al. Calcif Tissue Int (2003) 73: 380. doi:10.1007/s00223-002-2092-4

Abstract

The rare osteosclerotic disease, pycnodysostosis, is characterized by decreased osteoclastic bone collagen degradation due to the absence of active cathepsin K. Although this enzyme is primarily expressed by osteoclasts, there is increasing evidence that it may also be present in other cells, including fibroblasts. Since fibroblasts are known to degrade collagen intracellularly following phagocytosis, we analyzed various soft connective tissues (periosteum, perichondrium, tendon, and synovial membrane) from a 13-week-old human fetus with pycnodysostosis for changes in this collagen digestion pathway. In addition, the same tissues from cathepsin K-deficient and control mice were analyzed. Microscopic examination of the human fetal tissues showed that cross-banded collagen fibrils had accumulated in lysosomal vacuoles of fibroblasts. Morphometric analysis of periosteal fibroblasts revealed that the volume density of collagen-containing vacuoles was 18 times higher than in fibroblasts of control patients. A similar accumulation was seen in periosteal fibroblasts of three children with pycnodysostosis. In contrast to the findings in humans, an accumulation of internalized collagen was not apparent in fibroblasts of mice with cathepsin K deficiency. Our observations indicate that the intracellular digestion of phagocytosed collagen by fibroblasts is inhibited in humans with pycnodysostosis, but probably not in the mouse model mimicking this disease. The data strongly suggest that cathepsin K is a crucial protease for this process in human fibroblasts. Murine fibroblasts may have other proteolytic activities that are expressed constitutively or up regulated in response to a deficiency of cathepsin K. This may explain why cathepsin K-deficient mice lack the dysostotic features that are prominent in patients with pycnodysostosis.

Keywords

PycnodysostosisFibroblastCollagenCathepsin K

Copyright information

© Springer-Verlag 2003