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Ablation of Cathepsin K Activity in the Young Mouse Causes Hypermineralization of Long Bone and Growth Plates

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Abstract

Cathepsin K deficiency in humans causes pycnodysostosis, which is characterized by dwarfism and osteosclerosis. Earlier studies of 10-week-old male cathepsin K-deficient (knockout, KO) mice showed their bones were mechanically more brittle, while histomorphometry showed that both osteoclasts and osteoblasts had impaired activity relative to the wild type (WT). Here, we report detailed mineral and matrix analyses of the tibia of these animals based on Fourier transform infrared microspectroscopy and imaging. At 10 weeks, there was significant hypercalcification of the calcified cartilage and cortices in the KO. Carbonate content was elevated in the KO calcified cartilage as well as cortical and cancellous bone areas. These data suggest that cathepsin K does not affect mineral deposition but has a significant effect on mineralized tissue remodeling. Since growth plate abnormalities were extensive despite reported low levels of cathepsin K expression in the calcified cartilage, we used a differentiating chick limb-bud mesenchymal cell system that mimics endochondral ossification but does not contain osteoclasts, to show that cathepsin K inhibition during initial stages of mineral deposition retards the mineralization process while general inhibition of cathepsins can increase mineralization. These data suggest that the hypercalcification of the cathepsin K-deficient growth plate is due to persistence of calcified cartilage and point to a role of cathepsin K in bone tissue development as well as skeletal remodeling.

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Acknowledgments

This study was supported by National Institutes of Health grants AR037661, AR046121, and AR41210.

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Authors and Affiliations

  1. Musculoskeletal Integrity Program, Hospital for Special Surgery, 535 E 70th Street, New York, NY, 10021, USA

    Adele L. Boskey, Eric Pourmand, Valery Kudrashov, Stephen B. Doty & Lyudmila Spevak

  2. Mount Sinai School of Medicine, New York, NY, 10029, USA

    Bruce D. Gelb & Mitchell B. Schaffler

  3. City College of New York, New York, NY, 10031, USA

    Mitchell B. Schaffler

Authors
  1. Adele L. Boskey
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  2. Bruce D. Gelb
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  3. Eric Pourmand
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  4. Valery Kudrashov
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  5. Stephen B. Doty
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  6. Lyudmila Spevak
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  7. Mitchell B. Schaffler
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Correspondence to Adele L. Boskey.

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Boskey, A.L., Gelb, B.D., Pourmand, E. et al. Ablation of Cathepsin K Activity in the Young Mouse Causes Hypermineralization of Long Bone and Growth Plates. Calcif Tissue Int 84, 229–239 (2009). https://doi.org/10.1007/s00223-008-9214-6

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  • DOI: https://doi.org/10.1007/s00223-008-9214-6

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