Dai Rongchen, Wu Zeting, Chu Hang Yin, Lu Jun, Lyu Aiping, Liu Jin, Zhang Ge
Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, Hong Kong Baptist University, Hong Kong, China.
International Medical Service Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, China.
Front Cell Dev Biol. 2020 Jun 4;8:433. doi: 10.3389/fcell.2020.00433. eCollection 2020.
Cathepsin K (CatK) is one of the most potent proteases in lysosomal cysteine proteases family, of which main function is to mediate bone resorption. Currently, CatK is among the most attractive targets for anti-osteoporosis drug development. Although many pharmaceutical companies are working on the development of selective inhibitors for CatK, there is no FDA approved drug till now. Odanacatib (ODN) developed by Merck & Co. is the only CatK inhibitor candidate which demonstrated high therapeutic efficacy in patients with postmenopausal osteoporosis in Phase III clinical trials. Unfortunately, the development of ODN was finally terminated due to the cardio-cerebrovascular adverse effects. Therefore, it arouses concerns on the undesirable CatK inhibition in non-bone sites. It is known that CatK has far-reaching actions throughout various organs besides bone. Many studies have also demonstrated the involvement of CatK in various diseases beyond the musculoskeletal system. This review not only summarized the functional roles of CatK in bone and beyond bone, but also discussed the potential relevance of the CatK action beyond bone to the adverse effects of inhibiting CatK in non-bone sites.
组织蛋白酶K（CatK）是溶酶体半胱氨酸蛋白酶家族中最具活性的蛋白酶之一，其主要功能是介导骨吸收。目前，CatK是抗骨质疏松药物研发中最具吸引力的靶点之一。尽管许多制药公司都在致力于开发CatK的选择性抑制剂，但迄今为止尚无获得美国食品药品监督管理局（FDA）批准的药物。默克公司研发的odanacatib（ODN）是唯一一种在III期临床试验中对绝经后骨质疏松症患者显示出高治疗效果的CatK抑制剂候选药物。不幸的是，由于心脑血管不良反应，ODN的研发最终被终止。因此，人们开始关注在非骨部位对CatK的不良抑制作用。众所周知，除了骨骼之外，CatK在各个器官中都有广泛的作用。许多研究也表明，CatK参与了肌肉骨骼系统以外的各种疾病。这篇综述不仅总结了CatK在骨骼内外的功能作用，还讨论了CatK在骨骼外的作用与在非骨部位抑制CatK的不良反应之间的潜在相关性。
