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.