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Decreased Bone Turnover and Deterioration of Bone Structure in Two Cases of Pycnodysostosis

Ludwig Boltzmann Institute of Osteology, Fourth Medical Department, Hanusch Hospital and UKH-Meidling (N.F.-Z., A.V., P.R., A.N., K.K.), A-1140 Vienna, Austria; Erich Schmid Institute of Materials Sciences, Austrian Academy of Sciences and University of Leoben (A.V., P.F.), A-8700 Leoben, Austria; Institute for Pathology, Hanusch Hospital (A.N.), A-1140 Vienna, Austria; and Departments of Pediatrics and Human Genetics, Mount Sinai School of Medicine (B.D.G.), New York, New York 10029

Address all correspondence and requests for reprints to: Dr. Klaus Klaushofer, Ludwig Boltzmann Institute of Osteology, 4th Medical Department, Hanusch Hospital, Heinrich Collin Strasse 30, A-1140 Wien, Austria. E-mail: klaus.klaushofer{at}univie.ac.at.

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.

This work was supported in part by the AUVA (research funds of the Austrian workers compensation board), the WGKK (Viennice Sickness Insurance Fonds), and NIH Grant HD01294 (to B.D.G.). Part of this work was presented at the 24th American Society of Bone and Mineral Research Annual Meeting, San Antonio, TX, 2002.

Present address for P.F.: Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, D-14424 Potsdam, Germany.

Abbreviations: qBEI, Quantitative backscattered electron imaging; SAXS, small angle x-ray scattering; SEM, scanning electron microscope.

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