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

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