Abstract | 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.
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Authors | Lilian N Nwosu, Peter R W Gowler, James J Burston, Biljana Rizoska, Karin Tunblad, Erik Lindström, Urszula Grabowska, Li Li, Dan F McWilliams, David A Walsh, Victoria Chapman |
Journal | Pain reports
(Pain Rep)
Vol. 3
Issue 6
Pg. e685
(Nov 2018)
ISSN: 2471-2531 [Electronic] United States |
PMID | 30706033
(Publication Type: Journal Article)
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