Protective effects of a cathepsin K inhibitor, SB-553484, in the canine partial medial meniscectomy model of osteoarthritis
Protective effects of a cathepsin K inhibitor, SB-553484, in the canine partial medial meniscectomy model of osteoarthritis
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DOI：
10.1016/j.joca.2009.03.015
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发表时间：
2009-09-01
影响因子：
7
通讯作者：
Kumar, S.
中科院分区：
文献类型：
--
作者：
Connor, J. R.;LePage, C.;Kumar, S.
目的：组织蛋白酶K（cat K）是一种在破骨细胞、软骨细胞和滑膜成纤维细胞中表达的半胱氨酸蛋白酶，可降解几种骨和软骨基质成分，表明其在骨关节炎（OA）中的潜在作用。我们研究了SB-553484，猫K的抑制剂，对病变的严重程度和胶原降解的生物标志物在犬部分内侧anastrocectomy model.Methods的影响：一个部分内侧anastrocectomy在成熟的雌性比格犬进行。动物经口给予溶媒或SB-553484 50 mg/kg BID，持续28天。评价股胫关节的大体和显微镜下组织学变化。还分析了胶原蛋白降解的生物标志物。结果：在接受SB-553484治疗的犬中，主观大体和计算的变性评分分别显着下降29%和46%。组织学评价表明，胫骨退行性变总评分显著降低21%。抑制胫骨软骨退变是显着的1区（32%）和任何胫骨基质变化的深度比显着降低了28%。尿生物标志物的骨和软骨降解也显着reduced.Conclusion：治疗SB-553484导致轻度至中度的有益影响的总和组织病理学参数。I型胶原和II型胶原降解的生物标志物的减少表明该化合物对骨和软骨的直接影响。这些数据表明，通过抑制cat K来预防软骨降解可能代表了OA药理学干预的有效策略，并且监测胶原降解生物标志物可以提供抑制骨和软骨降解的保护作用的指示。(C)2009年国际骨关节炎研究学会。由爱思唯尔有限公司出版。保留所有权利。
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 50 mg/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.Conclusion: Treatment with SB-553484 resulted in mild to moderate beneficial effects on gross and histopathological parameters. Reduction of biomarkers of collagen type I and 11 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. (C) 2009 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.