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Analgesic effects of the cathepsin K inhibitor L-006235 in the monosodium iodoacetate model of osteoarthritis pain

Nwosu, Lilian N.; Gowler, Peter R.W.; Burston, James J.; Rizoska, Biljana; Tunblad, Karin; Lindström, Erik; Grabowska, Urszula; Li, Li; McWilliams, Dan F.; Walsh, David A.; Chapman, Victoria

Analgesic effects of the cathepsin K inhibitor L-006235 in the monosodium iodoacetate model of osteoarthritis pain Thumbnail


Authors

Lilian N. Nwosu

Peter R.W. Gowler

James J. Burston

Biljana Rizoska

Karin Tunblad

Erik Lindström

Urszula Grabowska

LI LI li.li@nottingham.ac.uk
Senior Research Fellow

DAVID WALSH david.walsh@nottingham.ac.uk
Professor of Rheumatology



Abstract

© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain. Introduction: The mounting evidence that osteoclasts play an important role in osteoarthritis (OA) pain lead us to investigate the effects of L-006235, a potent and selective inhibitor of cathepsin K, on pain behaviour and joint pathology in a model of OA pain. Methods: Effects of preventative (30 and 100 mg/kg) and therapeutic (100 mg/kg) oral dosing with L-006235 on weight-bearing asymmetry, hind paw withdrawal thresholds, cartilage and bone pathology, synovial inflammation, and drug exposure were studied in the monosodium iodoacetate rat model of OA pain. Results: Preventative L-006235 inhibited weight-bearing asymmetry from day 14, with this measure nearly abolished by the higher dose. In the same treatment setting, L-006235 prevented lowering of hind paw withdrawal thresholds from day 7. Exposure to L-006235 in plasma was higher for the 100 mg/kg dose, compared with 30 mg/kg. Therapeutic dosing with L-006235 from day 14 significantly inhibited weight-bearing asymmetry, compared with monosodium iodoacetate vehicle rats. Regression analysis revealed a significant interaction coefficient of the effects of L-006235 on weight-bearing asymmetry and synovitis score, but not for cartilage damage nor osteophyte scores. Conclusion: Our novel finding that cathepsin K inhibition is analgesic in a clinically relevant model of OA pain provides new evidence for the therapeutic potential of this target.

Citation

Nwosu, L. N., Gowler, P. R., Burston, J. J., Rizoska, B., Tunblad, K., Lindström, E., …Chapman, V. (2018). Analgesic effects of the cathepsin K inhibitor L-006235 in the monosodium iodoacetate model of osteoarthritis pain. PAIN Reports, 3(6), Article 685. https://doi.org/10.1097/PR9.0000000000000685

Journal Article Type Article
Acceptance Date Aug 16, 2018
Online Publication Date Oct 5, 2018
Publication Date Nov 1, 2018
Deposit Date Sep 5, 2018
Publicly Available Date Sep 5, 2018
Journal Pain Reports
Electronic ISSN 2471-2531
Publisher Lippincott, Williams & Wilkins
Peer Reviewed Peer Reviewed
Volume 3
Issue 6
Article Number 685
DOI https://doi.org/10.1097/PR9.0000000000000685
Public URL https://nottingham-repository.worktribe.com/output/1060699
Publisher URL https://journals.lww.com/painrpts/Abstract/latest/Analgesic_effects_of_the_cathepsin_K_inhibitor.99901.aspx
Contract Date Sep 5, 2018