Digoxin targets low density lipoprotein receptor-related protein 4 and protects against osteoarthritis.
Digoxin targets low density lipoprotein receptor-related protein 4 and protects against osteoarthritis.
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DOI：
10.1136/annrheumdis-2021-221380
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发表时间：
2022-04
影响因子：
27.4
通讯作者：
Liu, Chuan-ju
中科院分区：
文献类型：
--
作者：
Wang, Kai-di;Ding, Xiang;Jiang, Nan;Zeng, Chao;Wu, Jing;Cai, Xian-yi;Hettinghouse, Aubryanna;Khleborodova, Asya;Lei, Zi-Ning;Chen, Zhe-Sheng;Lei, Guang-hua;Liu, Chuan-ju
软骨细胞代谢失调与骨关节炎（OA）的发病机制密切相关。抑制软骨细胞增殖以恢复软骨稳态已被广泛探索，而对增强软骨细胞增殖的努力却少得多。本研究旨在重新利用临床批准的药物作为治疗OA的软骨细胞粘附的潜在刺激剂。食品和药物管理局批准的药物库的筛选;用于检查地高辛体外软骨保护作用的测定;用于使用药物诱导的OA模型确定地高辛治疗作用的测定;使用健康改善网络的倾向评分匹配队列研究，以检查房颤患者中地高辛使用与关节OA相关置换风险之间的关系;地高辛与低密度脂蛋白受体相关蛋白4（LRP 4）结合的鉴定和表征;各种测定，包括使用CRISPR-Cas9基因组编辑来删除人软骨细胞中的LRP 4，用于检查软骨细胞的地高辛调节对LRP 4的依赖性。一系列筛选导致哇巴因和地高辛作为软骨细胞分化和粘附的刺激剂的鉴定。哇巴因和地高辛可预防OA并缓解OA相关疼痛。对56,794例患者的队列研究显示，地高辛的使用与OA相关关节置换的风险降低相关。LRP 4被分离为地高辛的新靶点，并且LRP 4的缺失废除了地高辛对软骨细胞的调节。这些发现不仅为理解地高辛的软骨保护作用和潜在机制提供了新的见解，而且为重新利用地高辛治疗OA提供了新的证据。
Dysregulated chondrocyte metabolism is closely associated with the pathogenesis of osteoarthritis (OA). Suppressing chondrocyte catabolism to restore cartilage homeostasis has been extensively explored, whereas far less effort has been invested toward enhancing chondrocyte anabolism. This study aimed to repurpose clinically approved drugs as potential stimulators of chondrocyte anabolism in treating OA. Screening of a Food and Drug Administration-approved drug library; Assays for examining the chondroprotective effects of Digoxin in vitro; Assays for defining the therapeutic effects of Digoxin using a surgically-induced OA model; A propensity-score matched cohort study using The Health Improvement Network to examine the relationship between Digoxin use and the risk of joint OA-associated replacement among patients with atrial fibrillation; Identification and characterization of the binding of Digoxin to low density lipoprotein receptor-related protein 4 (LRP4); Various assays, including use of CRISPR-Cas9 genome editing to delete LRP4 in human chondrocytes, for examining the dependence on LRP4 of Digoxin regulation of chondrocytes. Serial screenings led to the identification of Ouabain and Digoxin as stimulators of chondrocyte differentiation and anabolism. Ouabain and Digoxin protected against OA and relieved OA-associated pain. The cohort study of 56,794 patients revealed that Digoxin use was associated with reduced risk of OA-associated joint replacement. LRP4 was isolated as a novel target of Digoxin, and deletion of LRP4 abolished Digoxin’s regulations of chondrocytes. These findings not only provide new insights into the understanding of Digoxin’s chondroprotective action and underlying mechanisms, but also present new evidence for repurposing Digoxin for OA.
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影响因子：
4.1
作者：
Kumar, Jitender;Swanberg, Maria;Akesson, Kristina
通讯作者：
Akesson, Kristina
影响因子：
27.4
作者：
Goldring MB;Otero M;Tsuchimochi K;Ijiri K;Li Y
通讯作者：
Li Y
影响因子：
4.9
作者：
Grogan SP;Miyaki S;Asahara H;D'Lima DD;Lotz MK
通讯作者：
Lotz MK
影响因子：
4
作者：
Cavalcante-Silva LHA;Lima ÉA;Carvalho DCM;de Sales-Neto JM;Alves AKA;Galvão JGFM;da Silva JSF;Rodrigues-Mascarenhas S
通讯作者：
Rodrigues-Mascarenhas S
DOI：
10.1038/nrrheum.2014.200
发表时间：
2015-04
期刊：
Nature reviews. Rheumatology
影响因子：
--
作者：
Jiang Y;Tuan RS
通讯作者：
Tuan RS