Format

Send to

Choose Destination
Calcif Tissue Int. 2019 Jan;104(1):92-101. doi: 10.1007/s00223-018-0472-7. Epub 2018 Sep 7.

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

Author information

1
Department of Clinical Cell Biology, Vejle Hospital/Lillebaelt Hospital, Institute of Regional Health Research, University of Southern Denmark, 7100, Vejle, Denmark.
2
Department of Clinical Cell Biology, Vejle Hospital/Lillebaelt Hospital, Institute of Regional Health Research, University of Southern Denmark, 7100, Vejle, Denmark. kent.soee@rsyd.dk.
3
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
4
Department of Biochemistry and Immunology, Vejle Hospital/Lillebaelt Hospital, Institute of Regional Health Research, University of Southern Denmark, 7100, Vejle, Denmark.
5
Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
6
Department of Clinical Cell Biology, Vejle Hospital/Lillebaelt Hospital, Institute of Regional Health Research, University of Southern Denmark, 7100, Vejle, Denmark. Jean-Marie.Delaisse@rsyd.dk.

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; Odanacatib; Osteoclast; Osteoporosis

PMID:
30194476
DOI:
10.1007/s00223-018-0472-7

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center