Pycnodysostosis is an uncommon human
genetic disorder characterized by
osteosclerosis of the skeleton, short stature, and bone fragility. The disease results from mutations in the
cathepsin K gene, a lysosomal
cysteine protease highly expressed in osteoclasts and crucial for the degradation of organic matrix from mineralized bone. Recently, interest has focused on a
pharmaceutical inhibition of
cathepsin K to prevent bone loss. However, little is known about the cellular activity or material quality of bone in
pycnodysostosis. In the present study, transiliac bone biopsies from two affected individuals, aged 5 and 21 yr, were investigated using light microscopy, quantitative backscattered electron imaging, and small angle x-ray scattering. Results were compared with published age-matched reference data. The mutations in the
cathepsin K gene of both patients were identified, including one novel defect. Both individuals had severe
osteosclerosis, and their biopsies displayed multinucleated osteoclasts apposed to areas of demineralized matrix as well as bone-lining cells adjacent to this undigested
collagen left over by osteoclasts. The homogeneity of the mineralized matrix was markedly disturbed due to large inclusions of mineralized cartilage residues. Histomorphometric evaluation showed a quantitative decrease in static parameters of bone formation. In contrast and despite deficient
cathepsin K activity, osteoclastic parameters were close to normal range. At the nanostructural level, there was a marked increase in the mean thickness of the
mineral particles, reflecting decreased bone remodeling. Examination of the trabecular structure revealed that the lamellae were highly disordered, which was also apparent from a poor alignment of
mineral crystals oriented along the longitudinal axis of
collagen fibrils. Taken together, these results strongly suggest that functional
cathepsin K is important for balanced bone turnover, and
enzyme deficiency results in a profound deterioration of bone quality with respect to trabecular architecture and lamellar arrangement, which is presumably the reason for bone fragility in
pycnodysostosis.