Kim Gyeong Min, Park Doo Ri, Nguyen Thi Thu Ha, Kim Jiseon, Kim Jihee, Sohn Myung-Ho, Lee Won-Kyu, Lee Soo Young, Shim Hyunbo
Department of Life Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
The Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 03760, Republic of Korea.
Biomedicines. 2023 Oct 19;11(10):2844. doi: 10.3390/biomedicines11102844.
Osteoarthritis (OA) is the most common joint disease that causes local inflammation and pain, significantly reducing the quality of life and normal social activities of patients. Currently, there are no disease-modifying OA drugs (DMOADs) available, and treatment relies on pain relief agents or arthroplasty. To address this significant unmet medical need, we aimed to develop monoclonal antibodies that can block the osteoclast-associated receptor (OSCAR). Our recent study has revealed the importance of OSCAR in OA pathogenesis as a novel catabolic regulator that induces chondrocyte apoptosis and accelerates articular cartilage destruction. It was also shown that blocking OSCAR with a soluble OSCAR decoy receptor ameliorated OA in animal models. In this study, OSCAR-neutralizing monoclonal antibodies were isolated and optimized by phage display. These antibodies bind to and directly neutralize OSCAR, unlike the decoy receptor, which binds to the ubiquitously expressed collagen and may result in reduced efficacy or deleterious off-target effects. The DMOAD potential of the anti-OSCAR antibodies was assessed with in vitro cell-based assays and an in vivo OA model. The results demonstrated that the anti-OSCAR antibodies significantly reduced cartilage destruction and other OA signs, such as subchondral bone plate sclerosis and loss of hyaline cartilage. Hence, blocking OSCAR with a monoclonal antibody could be a promising treatment strategy for OA.
骨关节炎（OA）是最常见的关节疾病，可导致局部炎症和疼痛，严重降低患者的生活质量和正常社交活动。目前，尚无改善病情的骨关节炎药物（DMOADs），治疗依赖于止痛剂或关节成形术。为满足这一重大未满足的医疗需求，我们旨在开发能够阻断破骨细胞相关受体（OSCAR）的单克隆抗体。我们最近的研究揭示了OSCAR在OA发病机制中的重要性，它是一种新型分解代谢调节因子，可诱导软骨细胞凋亡并加速关节软骨破坏。研究还表明，用可溶性OSCAR诱饵受体阻断OSCAR可改善动物模型中的OA。在本研究中，通过噬菌体展示分离并优化了OSCAR中和单克隆抗体。与诱饵受体不同，这些抗体与OSCAR结合并直接中和它，诱饵受体与普遍表达的胶原蛋白结合，可能导致疗效降低或产生有害的脱靶效应。用基于细胞的体外试验和体内OA模型评估了抗OSCAR抗体的DMOAD潜力。结果表明，抗OSCAR抗体显著减少了软骨破坏和其他OA体征，如软骨下骨板硬化和透明软骨丧失。因此，用单克隆抗体阻断OSCAR可能是一种有前景的OA治疗策略。
