Digoxin targets low density lipoprotein receptor-related protein 4 and protects against osteoarthritis.

Autor:	Wang KD; Department of Orthopedic Surgery, New York University Grossman School of Medicine, New York, New York, USA., Ding X; Department of Orthopedic Surgery, New York University Grossman School of Medicine, New York, New York, USA.; Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, China., Jiang N; Department of Orthopedic Surgery, New York University Grossman School of Medicine, New York, New York, USA., Zeng C; Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, China.; Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, Hunan, China., Wu J; Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, Hunan, China., Cai XY; Department of Orthopedic Surgery, New York University Grossman School of Medicine, New York, New York, USA., Hettinghouse A; Department of Orthopedic Surgery, New York University Grossman School of Medicine, New York, New York, USA., Khleborodova A; Department of Orthopedic Surgery, New York University Grossman School of Medicine, New York, New York, USA., Lei ZN; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, New York, USA., Chen ZS; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, New York, USA., Lei GH; Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, China lei_guanghua@csu.edu.cn chuanju.liu@nyumc.org.; Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, Hunan, China., Liu CJ; Department of Orthopedic Surgery, New York University Grossman School of Medicine, New York, New York, USA lei_guanghua@csu.edu.cn chuanju.liu@nyumc.org.; Department of Cell Biology, New York University Grossman School of Medicine, New York, New York, USA.
Jazyk:	angličtina
Zdroj:	Annals of the rheumatic diseases [Ann Rheum Dis] 2022 Apr; Vol. 81 (4), pp. 544-555. Date of Electronic Publication: 2021 Dec 01.
DOI:	10.1136/annrheumdis-2021-221380
Abstrakt:	Objectives: 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. Methods: 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 characterisation 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. Results: 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. Conclusions: 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. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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