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

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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.

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Authors and Affiliations

  1. Department of Cell Biology and Histology, Academic Medical Centre, University of Amsterdam, 1100 DE Amsterdam, The Netherlands

    V. Everts & W. Tigchelaar

  2. Department of Periodontology, Academic Centre for Dentistry, University of Amsterdam, Amsterdam, The Netherlands

    V. Everts & W. Beertsen

  3. Department of Human Genetics, Mount Sinai School of Medicine, New York, NY, USA

    W. S. Hou, D. Brömme & B. D. Gelb

  4. Department of Paediatrics, Centre Hospitalier Universitaire d’Angers, France

    X. Rialland

  5. Biochemical Institute, Christian-Albrechts University, Kiel, Germany

    P. Saftig

  6. Department of Pediatrics, Mount Sinai School of Medicine, New York, NY, USA

    B. D. Gelb

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  1. V. Everts
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  8. W. Beertsen
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Correspondence to V. Everts.

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Everts, V., Hou, W., Rialland, X. et al. Cathepsin K Deficiency in Pycnodysostosis Results in Accumulation of Non-Digested Phagocytosed Collagen in Fibroblasts . Calcif Tissue Int 73, 380–386 (2003). https://doi.org/10.1007/s00223-002-2092-4

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  • DOI: https://doi.org/10.1007/s00223-002-2092-4

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