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Digoxin targets low density lipoprotein receptor-related protein 4 and protects against osteoarthritis
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  • Published on:
    Response to ‘Correspondence on ‘Digoxin targets low density lipoprotein receptor-related protein 4 and protects against osteoarthritis’ by Kai-di Wang’ by Cheng et al
    • Kai-di Wang, Post doctoral fellow Department of Orthopedic Surgery, NYU Grossman School of Medicine, New York, New York, USA
    • Other Contributors:
      • Xiang Ding, PhD student
      • Chuan-ju Liu, Professor

    We thank Cheng et al1 for their interest in our paper ‘Digoxin targets low density lipoprotein receptor-related protein 4 and protects against osteoarthritis’.2 Below we provide point-by-point replies to the comments.
    First, we would like to clarify the roles of digoxin and ouabain in this study. We performed three rounds of drug screening and found that only ouabain could robustly induce the expressions of anabolic marker genes, including COL2A1, aggrecan (ACAN) and cartilage oligomeric matrix protein (COMP).3,4 The fact that ouabain belongs to a family of cardenolides prompted us to determine whether other cardenolides also possess the similar anabolic effects in chondrocytes, which led to the isolation of digoxin as another cardenolide that could also induce the expressions of anabolic marker genes in chondrocytes. We appreciate the author’s statement that ouabain demonstrated better protection against OA in some assays mentioned in their correspondence. However, digoxin also showed significant protective effects against OA in multiple analyses performed, quite similar to ouabain. For instance, there is no difference in the osteophyte number between digoxin and ouabain treatment groups (Figure 2F and 2G). More importantly, digoxin is known to be the only safe inotropic drug for oral use that improves hemodynamics.5 This led us to hypothesize that records related to digoxin might be accessible in general practitioner based medical records databases. Indeed, we foun...

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    Conflict of Interest:
    None declared.
  • Published on:
    Digoxin targets low density lipoprotein receptor-related protein 4 and protects against osteoarthritis
    • Yunzhong Cheng, Orthopedic Surgeon Department of Orthopedic Surgery, Beijing Chao-Yang Hospital, Capital Medical University
    • Other Contributors:
      • Lijin Zhou, Orthopedic Surgeon
      • Yong Hai, Professor and Chairman

    We read with great interest the recent study by Kai-di Wang and colleagues1, published in the Annals of Rheumatic Disease, which showed LRP4 was isolated as a novel target of digoxin, and deletion of LRP4 abolished digoxin’s regulations of chondrocytes. We appreciate this meaningful research very much, and we believe that this study has significant guiding for providing new insights into the understanding of digoxin’s chondroprotective action and underlying mechanisms, but also present new evidence for repurposing digoxin for osteoarthritis (OA). However, we have some questions to discuss with the authors except for the limitations the authors mentioned in the study.
    As all we know, the authors used two cardenolides to conduct the experiments, ouabain and digoxin. We can know that ouabain and digoxin can both enhance chondrogenesis and stimulate chondrocyte anabolism from the result of Figure 1. More importantly, we found that the relative staining level in ouabain treated groups was much higher compared with that in digoxin group (Figure 1B). Moreover, the mRNA expressions of transcriptional levels of chondrogenic marker genes, such as COL2A1, Comp, ACAN, SOX5, SOX6, and SOX92-4 were also much higher compared with that in digoxin group (Figure 1C). The similar situation was showed in Figure 1D-G, which may indicate ouabain better enhance chondrogenesis and stimulate chondrocyte anabolism than that of digoxin. In addition, we may also speculate ouabain bette...

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    Conflict of Interest:
    None declared.