Inhibition of cathepsin K reduces cartilage degeneration in the anterior cruciate ligament transection rabbit and murine models of osteoarthritis

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• 作者：Tadashi Hayami¹ ; Ya Zhuo ; Gregg A. Wesolowski ; Maureen Pickarski ; Le T. Duong ; ^{le.duong@merck.com}
• 关键词：Osteoarthritis ; Cathepsin K inhibition ; Articular cartilage ; Subchondral bone ; Osteophytes
• 刊名：Bone
• 出版年：2012
• 期刊代码：39_87563282
• 类别：med
• 出版时间：June, 2012
• 卷：50
• 期：6
• 页码：1250-1259
• 文件大小：2193 K

摘要

Objective

To investigate the disease modifying effects of cathepsin K (CatK) inhibitor L-006235 compared to alendronate (ALN) in two preclinical models of osteoarthritis (OA).

Methods

Skeletally mature rabbits underwent sham or anterior cruciate ligament transection (ACLT)-surgery and were treated with L-006235 (L-235, 10 mg/kg or 50 mg/kg, PO, daily) or ALN (0.6 mg/kg, s.c., weekly) for 8-weeks. ACLT joint instability was also induced in CatK^{鈭?鈭?/sup> versus wild type (wt) mice and treated for 16-weeks. Changes in cartilage degeneration, subchondral bone volume and osteophyte area were determined by histology and 渭-CT. Collagen type I helical peptide (HP-I), a bone resorption marker and collagen type II C-telopeptide (CTX-II), a cartilage degradation marker were measured.}

Results

L-235 (50 mg/kg) and ALN treatment resulted in significant chondroprotective effects, reducing CTX-II by 60%and the histological Mankin score for cartilage damage by 46%in the ACLT-rabbits. Both doses of L-235 were more potent than ALN in protecting against focal subchondral bone loss, and reducing HP-I by 70%compared to vehicle. L-235 (50 mg/kg) and ALN significantly reduced osteophyte formation in histomorphometric analysis by 55%. The Mankin score in ACLT-CatK^{鈭?鈭?/sup> mice was ~ 2.5-fold lower than the ACLT-wt mice and was not different from sham-CatK鈭?鈭?/sup>. Osteophyte development was not different among the groups.}

Conclusion

Inhibition of CatK provides significant benefits in ACLT-model of OA, including: 1) protection of subchondral bone integrity, 2) protection against cartilage degradation and 3) reduced osteophytosis. Preclinical evidence supports the role of CatK as a potential therapeutic target for the treatment of OA.