Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Orthopaedic Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China.
Orthopaedic Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China; Department of Joint Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
Int Immunopharmacol. 2024 Dec 5;142(Pt B):113158. doi: 10.1016/j.intimp.2024.113158. Epub 2024 Sep 17.
Osteolysis in Rheumatoid arthritis (RA) is principally provoked by osteoclast hyperactivity. This study aims to employ Corydaline (Cory), a plant extract, as an osteoclast inhibitor in treating RA-inflicted osteolysis while unveiling the corresponding mechanism.
Osteoclasts were derived from mouse bone marrow-derived monocytes (BMMs) stimulated with M-CSF and RANKL. Subsequently, utilizing network pharmacology, we performed a thorough analysis of Cory's molecular structure and discerned its preliminary therapeutic potential. Subsequently, LPS was used to simulate and establish an in vitro model of RA, and the biological effect of Cory on osteoclast behaviors was evaluated through various staining methods, RT-qPCR, and Western blot. In addition, a collagen-induced arthritis (CIA) mouse model was developed to evaluate the therapeutic effects of Cory in vivo.
The results from network pharmacology indicated a significant correlation between Cory, oxidative stress, and calcium signaling. Subsequent in vitro experiments demonstrated Cory's capacity to inhibit the formation and function of osteoclast under inflammatory stimuli, thereby protecting against abnormal bone resorption. This effect is achieved by activating the Nrf2 signaling pathway, mitigating the generation of reactive oxygen species (ROS), and modulating the calcineurin-Nfatc1 signaling. Furthermore, this therapeutic effect of Cory on RA-associated osteolysis was proved in CIA mice models.
Cory demonstrates the potential to activate the Nrf2 signaling pathway, effectively countering oxidative stress, and simultaneously inhibit the calcineurin-Nfatc1 signaling pathway to regulate the terminals of calcium signaling. These dual effects collectively reduce osteoclast activity, ultimately contributing to a therapeutic role in RA osteolysis. Therefore, our study presents Cory as a novel pharmaceutical candidate for the prevention and treatment of RA.
类风湿关节炎（RA）中的骨溶解主要由破骨细胞活性亢进引起。本研究旨在利用苦参碱（Cory）作为破骨细胞抑制剂治疗 RA 引起的骨溶解，并揭示相应的机制。
用 M-CSF 和 RANKL 刺激小鼠骨髓来源的单核细胞（BMMs）衍生破骨细胞。然后，我们通过网络药理学对 Cory 的分子结构进行了全面分析，并确定了其初步的治疗潜力。随后，用 LPS 模拟并建立 RA 的体外模型，通过各种染色方法、RT-qPCR 和 Western blot 评估 Cory 对破骨细胞行为的生物学影响。此外，建立胶原诱导性关节炎（CIA）小鼠模型，评估 Cory 在体内的治疗效果。
网络药理学的结果表明 Cory 与氧化应激和钙信号之间存在显著相关性。随后的体外实验表明，Cory 在炎症刺激下能够抑制破骨细胞的形成和功能，从而防止异常的骨吸收。这种作用是通过激活 Nrf2 信号通路、减轻活性氧（ROS）的产生以及调节钙调神经磷酸酶-Nfatc1 信号来实现的。此外，Cory 在 CIA 小鼠模型中对 RA 相关骨溶解的治疗效果也得到了证实。
Cory 具有激活 Nrf2 信号通路的潜力，有效对抗氧化应激，同时抑制钙调神经磷酸酶-Nfatc1 信号通路以调节钙信号的末端。这两种作用共同降低破骨细胞活性，最终在 RA 骨溶解的治疗中发挥作用。因此，我们的研究表明 Cory 是一种用于预防和治疗 RA 的新型药物候选物。
