A Mild Inhibition of Cathepsin K Paradoxically Stimulates the Resorptive Activity of Osteoclasts in Culture
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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.
KeywordsBone resorption Cathepsin K Osteoporosis Odanacatib Osteoclast
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.
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.
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).
All participants in this study provided written informed consent.
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