Protective effects of a cathepsin K inhibitor, SB-553484, in the canine partial medial meniscectomy model of osteoarthritis.
OBJECTIVE
Cathepsin K (cat K), a cysteine protease expressed in osteoclasts, chondrocytes and synovial fibroblasts, degrades several bone and cartilage matrix components suggesting its potential role in osteoarthritis (OA). We investigated the effects of SB-553484, an inhibitor of cat K, on lesion severity and biomarkers of collagen degradation in the canine partial medial meniscectomy model.


METHODS
A partial medial meniscectomy was performed in mature female beagle dogs. Animals were dosed orally with vehicle or SB-553484 at 50mg/kg BID for 28 days. The femorotibial joints were evaluated for gross and microscopic histological changes. Biomarkers of collagen degradation were also analyzed.


RESULTS
In dogs treated with SB-553484, subjective gross and calculated degeneration scores decreased significantly by 29% and 46%, respectively. Histopathologic evaluation demonstrated that the summed tibial degeneration score decreased significantly by 21%. Inhibition of tibial cartilage degeneration was significant in zone 1 (32%) and the depth ratio of any tibial matrix change was decreased significantly by 28%. Urinary biomarkers of bone and cartilage degradation were also significantly reduced.


CONCLUSIONS
Treatment with SB-553484 resulted in mild to moderate beneficial effects on gross and histopathological parameters. Reduction of biomarkers of collagen type I and II degradation indicated a direct effect of the compound on bone and cartilage. These data suggest that the prevention of cartilage degradation by cat K inhibition may represent a valid strategy for pharmacological intervention in OA and that monitoring collagen degradation biomarkers may provide an indication of the protective effects of inhibition of bone and cartilage degradation.
Connor
J R
JR
Immuno-Inflammation, GlaxoSmithKline Pharmaceuticals, Collegeville, PA 19426, USA. janice.r.connor@gsk.com
LePage
C
C
Swift
B A
BA
Yamashita
D
D
Bendele
A M
AM
Maul
D
D
Kumar
S
S
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002358:Cartilage, Articular / Q000187:drug effects*; D056657:Cathepsin K; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism*; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D010003:Osteoarthritis / Q000378:metabolism*; D011725:Pyridines / Q000378:metabolism*; D013223:Statistics as Topic
D015415:Biomarkers; D015853:Cysteine Proteinase Inhibitors; D011725:Pyridines; C524569:SB-553484; D056657:Cathepsin K