Cathepsin K inhibition reduces CTXII levels and joint pain in the guinea pig model of spontaneous osteoarthritis.
Cathepsin K is a cysteine proteinase which is believed to contribute to osteoarthritis (OA) pathogenesis. This brief report evaluates the effect of the novel selective cathepsin K inhibitor AZ12606133 on cartilage metabolism in the Dunkin-Hartley guinea pig model of spontaneous OA. In parallel, electrophysiological studies were performed to determine whether acute and chronic treatment with the cathepsin K inhibitor could alter joint nociception. Acute treatment of OA knees with AZ12606133 had no effect on joint afferent nerve activity; however, prolonged (1 month) administration of the cathepsin K inhibitor delivered via a chronically implanted osmotic pump significantly reduced mechanosensitivity in response to both non-noxious and noxious joint movements. Urinal concentrations of the cartilage breakdown products cross-linked C-telopeptides of type II collagen (CTXII) were also reduced by chronic cathepsin K inhibition. These data suggest that prolonged AZ12606133 administration can reduce cartilage turnover and joint nociception in the Dunkin-Hartley guinea pig model of spontaneous OA.
McDougall
J J
JJ
Department of Physiology & Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada. mcdougaj@ucalgary.ca
Schuelert
N
N
Bowyer
J
J
D000818:Animals; D001169:Arthritis, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism; D056657:Cathepsin K / Q000037:antagonists & inhibitors*; D024043:Collagen Type II / Q000652:urine*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006168:Guinea Pigs; D007596:Joints / Q000294:innervation; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D010003:Osteoarthritis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D010446:Peptide Fragments / Q000652:urine*
D024043:Collagen Type II; D010446:Peptide Fragments; C543437:collagen II C-telopeptide; D056657:Cathepsin K