Pharmacological inhibition of cathepsin K: A promising novel approach for postmenopausal osteoporosis therapy

详细信息    查看全文

• 作者：Kakoli Mukherjee^a ; ^b ; ^{kakoli.mukherjee@ibs.net.in" class="auth_mail" title="E-mail the corresponding author} ; Naibedya Chattopadhyay^c ; ^{n_chattopadhyay@cdri.res.in" class="auth_mail" title="E-mail the corresponding author}
• 关键词：CatK ; cathepsin K ; ODN ; odanacatib ; BMD ; bone mineral density ; DXA ; dual X-ray absorptiometry ; RANKL ; receptor activator of nuclear factor kappB ligand ; OP ; osteoporosis ; OA ; osteoarthritis ; MBD ; metastatic bone disease ; DHT ; p-dihydrotanshinone ; CTx/CTX ; collagen type 1 cross-linked C-telopeptide ; NTx/NTX ; N-terminal telopeptide ; BMC ; bone mineral content ; BFR ; bone formation rate ; TRAP ; tartrate-resistant acid phosphatase ; QCT ; quantitative computed tomography ; MC ; Metachondromatosis
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：1 October 2016
• 年：2016
• 卷：117
• 期：Complete
• 页码：10-19
• 全文大小：796 K

文摘

Osteoporosis is a metabolic bone disease that is characterized by heightened state of bone resorption accompanied by diminished bone formation, leading to a reduction of bone mineral density (BMD) and deterioration of bone quality, thus increasing the risk of developing fractures. Molecular insight into bone biology identified cathepsin K (CatK) as a novel therapeutic target. CatK is a lysosomal cysteine protease secreted by activated osteoclasts during bone resorption, whose primary substrate is type I collagen, the major component of organic bone matrix. Available anti-resorptive drugs affect osteoclast survival and influence both resorption and formation of bone. CatK inhibitors are distinct from the existing anti-resorptives as they only target the resorption process itself without impairing osteoclast differentiation and do not interfere with bone formation. An inhibitor of CatK, odanacatib, robustly increased both trabecular and cortical BMD in postmenopausal osteoporosis patients. The phase III fracture prevention trial with odanacatib ended early due to good efficacy and a favorable benefit/risk profile, thus, enhancing the opportunity for CatK as a pharmacological target for osteoporosis. So far, all the inhibitors that reached to the stage of clinical trial targeted active site of CatK to abrogate the entire proteolytic activity of the enzyme in addition to the desired blockage of excessive elastin and collagen degradation, and could thus pose safety concerns with long term use. Identification of selective exosite inhibitors that inhibit CatK’s elastase and/or collagenase activity but do not affect the hydrolysis of other physiologically relevant substrates of CatK would be an improved strategy to inhibit this enzyme.