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Digoxin targets low density lipoprotein receptor-related protein 4 and protects against osteoarthritis
  1. Kai-di Wang1,
  2. Xiang Ding1,2,
  3. Nan Jiang1,
  4. Chao Zeng2,3,
  5. Jing Wu3,
  6. Xian-yi Cai1,
  7. Aubryanna Hettinghouse1,
  8. Asya Khleborodova1,
  9. Zi-Ning Lei4,
  10. Zhe-Sheng Chen4,
  11. Guang-hua Lei2,3,
  12. Chuan-ju Liu1,5
  1. 1 Department of Orthopedic Surgery, New York University Grossman School of Medicine, New York, New York, USA
  2. 2 Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, China
  3. 3 Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, Hunan, China
  4. 4 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, New York, New York, USA
  5. 5 Department of Cell Biology, New York University Grossman School of Medicine, New York, New York, USA
  1. Correspondence to Professor Guang-hua Lei, Department of Orthopaedics, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, China, 410008; lei_guanghua{at}csu.edu.cn; Dr Chuan-ju Liu, Rm 1608, Department of Orthopedic Surgery, NYU Langone Orthopedic Hospital, 301 East 17th Street, New York, New York10003, USA; chuanju.liu{at}nyumc.org

Abstract

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.

  • osteoarthritis
  • chondrocytes
  • therapeutics

Data availability statement

All data relevant to the study are included in the article. Not applicable.

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Data availability statement

All data relevant to the study are included in the article. Not applicable.

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Footnotes

  • Handling editor Josef S Smolen

  • K-dW and XD contributed equally.

  • Contributors K-dW and XD designed and performed the experiments, collected and analysed the data and drafted the manuscript. NJ and X-yC participated in chondrogenesis-related experiments and identification of the drug target. CZ and JW performed the cohort study. AH assisted with human sample collection and language modification. AK participated in drug screening. Z-nL and Z-sC performed the induced-fit docking simulations. G-hL had full access to the database in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. C-jL had the concept, supervised all of the experiments and revised the manuscript. C-jL as the guarantor and responseible for the overall content. All authors have read, provided critical feedback on intellectual content and approved the final manuscript.

  • Funding This work is supported partly by NIH research grants R01AR062207, R01AR061484, R01AR076900, R01NS103931 and a DOD research grant W81XWH-16-1-0482.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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