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Calcified Tissue International

, Volume 104, Issue 1, pp 92–101 | Cite as

A Mild Inhibition of Cathepsin K Paradoxically Stimulates the Resorptive Activity of Osteoclasts in Culture

  • Dinisha Cyril Pirapaharan
  • Kent SøeEmail author
  • Preety Panwar
  • Jonna Skov Madsen
  • Marianne Lerbæk Bergmann
  • Martin Overgaard
  • Dieter Brömme
  • Jean-Marie DelaisseEmail author
Original Research

Abstract

Cathepsin K (CatK) inhibition allows reducing bone resorption with specific advantages compared to the existing anti-osteoporosis drugs. Its clinical use appears even more promising with the recent development of ectosteric inhibitors. A confusing observation, however, is that a low dose of the active site CatK inhibitor odanacatib (ODN) was reported to decrease bone mineral density and increase serum levels of the bone resorption marker carboxy-terminal collagen crosslinks (CTX). The present study provides a possible explanation for this paradox. The resorptive activity of human osteoclasts seeded on bone slices was inhibited when subjected to ODN at doses of 20 nM, but about 100-fold lower doses induced a significant increase in CTX levels and in eroded surface (12 repeats). This low-dose-induced stimulation was prevented by inhibition of non-CatK cysteine proteinases, thereby indicating that the stimulation results from an interplay between CatK and other cysteine proteinases. Effective interplay between these proteinases was also shown in enzymatic assays where the CatK-mediated degradation of collagen was enhanced upon addition of cathepsins B or L. Furthermore, extracts of osteoclasts subjected to a low dose of ODN showed higher levels of cathepsin B compared with extracts of control osteoclasts. In conclusion, the low-dose-induced stimulation of resorption observed in the clinical study can be reproduced in osteoclasts cultured in the absence of any other cell. Our data support an osteoclast-intrinsic mechanism where a mild inhibition of CatK results in increased levels of other proteinases contributing to the collagen degradation process.

Keywords

Bone resorption Cathepsin K Osteoporosis Odanacatib Osteoclast 

Notes

Acknowledgements

We thank Jacob Bastholm Olesen for excellent technical assistance and Anne V Schmedes and Merete Villiumsen for her kind assistance on biochemical procedures. This study has received financial support from The Region of Southern Denmark (Grant No. 13/27663), Vejle Hospital/Lillebaelt Hospital and the University of Southern Denmark.

Author Contributions

Designing the study: DCP, KS, and J-MD; conducting experiments: DCP, PP, and KS; acquiring data: DCP, PP, MO, MLB, JSM, and KS; analyzing data: DCP, PP, DB, MO, KS, and J-MD; writing the manuscript: DCP, KS, and J-MD; editing and correcting the manuscript: all authors; final approval of manuscript: all authors.

Compliance with Ethical Standards

Conflict of interest

Dinisha Cyril Pirapaharan, Kent Søe, Preety Panwar, Jonna Skov Madsen, Marianne Lerbæk Bergmann, Martin Overgaard, Dieter Brömme, and Jean-Marie Delaisse declare that they have no conflict of interest.

Ethical Approval

The study has been performed in accordance with the ethical standards and was approved by The Regional Committees on Health Research Ethics for Southern Denmark (approval number. 2007–0019).

Informed Consent

All participants in this study provided written informed consent.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Dinisha Cyril Pirapaharan
    • 1
  • Kent Søe
    • 1
    Email author
  • Preety Panwar
    • 2
  • Jonna Skov Madsen
    • 3
  • Marianne Lerbæk Bergmann
    • 3
  • Martin Overgaard
    • 4
  • Dieter Brömme
    • 2
  • Jean-Marie Delaisse
    • 1
    Email author
  1. 1.Department of Clinical Cell Biology, Vejle Hospital/Lillebaelt Hospital, Institute of Regional Health ResearchUniversity of Southern DenmarkVejleDenmark
  2. 2.Department of Biochemistry and Molecular Biology, Faculty of MedicineUniversity of British ColumbiaVancouverCanada
  3. 3.Department of Biochemistry and Immunology, Vejle Hospital/Lillebaelt Hospital, Institute of Regional Health ResearchUniversity of Southern DenmarkVejleDenmark
  4. 4.Department of Clinical Biochemistry and PharmacologyOdense University HospitalOdenseDenmark

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