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

Dinisha Cyril Pirapaharan, Kent Søe, Preety Panwar, Jonna Skov Madsen, Marianne Lerbæk Bergmann, Martin Overgaard, Dieter Brömme, Jean-Marie Delaisse*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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.

Original languageEnglish
JournalCalcified Tissue International
Volume104
Issue number1
Pages (from-to)92-101
ISSN0171-967X
DOIs
Publication statusPublished - Jan 2019

Keywords

  • Bone resorption
  • Cathepsin K
  • Odanacatib
  • Osteoclast
  • Osteoporosis

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