digoxin and Osteoarthritis

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Cardiotonic Agents; Comorbidity; Digoxin; Disease Progression; Diuretics; Drug Monitoring; Geriatric Nursing; Heart Failure; Humans; Nursing Homes; Osteoarthritis; Patient Selection; Pulmonary Disease, Chronic Obstructive

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 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.. 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.

Topics: Cartilage, Articular; Chondrocytes; Cohort Studies; Digoxin; Drug Repositioning; Humans; LDL-Receptor Related Proteins; Osteoarthritis; Ouabain

Relatively low-grade inflammatory of osteoarthritic joints is characterized by synovitis and a catabolic and proinflammatory state of the chondrocytes and plays an important role in osteoarthritis (OA) initiation and exacerbation. Our previous research showed cardiac glycoside compounds might be effective in OA synovitis. However, the effect of digoxin (DIG), an FDA-approved cardenolide, on inflammation inhibition of osteoarthritic joints has not been investigated. In the present study, a western blot analysis and immunofluorescence staining revealed that DIG alleviated OA synovitis by inhibiting the M1-like polarization of synovial macrophages in OA patients and collagenase-induced OA (CIOA, with considerable synovitis) mice. Subsequently, the exosomes produced by macrophages and M1-like macrophages treated with or without DIG were isolated and identified. According to miRNA sequencing analysis of these exosomes and subsequent target activity assays, we confirmed DIG controls OA inflammatory microenvironment and promotes chondrogenesis by, at least partly, downregulating the M1-like macrophage-derived exosomal miR-146b-5p/Usp3&Sox5 axis in vitro and in vivo. This research provides reliable experimental evidence supporting the clinical application of DIG as a disease-modifying drug for inflammation-associated OA. Additionally, the spectrum of diseases of inflammation controlled by DIG has been broadened, which prompting research interest in the new function of an "old" FDA-approved drug.

Topics: Animals; Digoxin; Inflammation; Macrophages; Mice; MicroRNAs; Osteoarthritis; Synovitis

Compounds with specific cytotoxic activity in senescent cells, or senolytics, support the causal involvement of senescence in aging and offer therapeutic interventions. Here we report the identification of Cardiac Glycosides (CGs) as a family of compounds with senolytic activity. CGs, by targeting the Na+/K+ATPase pump, cause a disbalanced electrochemical gradient within the cell causing depolarization and acidification. Senescent cells present a slightly depolarized plasma membrane and higher concentrations of H+, making them more susceptible to the action of CGs. These vulnerabilities can be exploited for therapeutic purposes as evidenced by the in vivo eradication of tumors xenografted in mice after treatment with the combination of a senogenic and a senolytic drug. The senolytic effect of CGs is also effective in the elimination of senescence-induced lung fibrosis. This experimental approach allows the identification of compounds with senolytic activity that could potentially be used to develop effective treatments against age-related diseases.

Topics: A549 Cells; Animals; Antibiotics, Antineoplastic; Apoptosis; Bleomycin; Breast Neoplasms; Cardiac Glycosides; Cell Line, Tumor; Cell Membrane; Cellular Senescence; Chondrocytes; Digoxin; Female; Fibroblasts; Humans; Hydrogen-Ion Concentration; Mice; Osteoarthritis; Ouabain; Proscillaridin; Pulmonary Fibrosis; Xenograft Model Antitumor Assays

The isoprenoid pathway produces three key metabolites: i) digoxin (a membrane sodium-potassium ATPase inhibitor which can regulate intracellular calcium/magnesium ratios), ii) dolichol (which regulates N-glycosylation of proteins), and iii) ubiquinone (a free radical scavenger), all of which are important in bone and joint metabolism. The pathway was assessed in senile osteoporosis, spondylosis, and osteoarthritis. Digoxin could possibly play a role in the genesis of cerebral dominance because it can regulate multiple neurotransmitter systems. The pathway was also assessed in individuals of differing hemispheric dominance for comparison and to find out the role of cerebral dominance in the pathogenesis of these diseases. The plasma/serum-activity of HMG CoA reductase, magnesium, digoxin, dolichol, ubiquinone, and tryptophan/tyrosine catabolic patterns, as well as RBC Na(+)-K+ ATPase activity, were measured in the above mentioned groups. The glycoconjugate metabolism, free radical metabolism, and membrane composition were also studied. The pathway was upregulated with increased digoxin synthesis in patients with spondylosis and osteoarthritis. In this group of patients, the glycoconjugate levels and dolichol levels were increased and lysosomal stability reduced. The ubiquinone levels were low and free radicals increased in spondylosis and osteoarthritis. On the other hand, in senile osteoporosis, the isoprenoid pathway was downregulated and digoxin synthesis reduced. The glycoconjugate and dolichol levels were low and lysosomal stability increased. The ubiquinone levels were increased and free radical production increased in senile osteoporosis. The significance of these changes in the pathogenesis of osteoarthritis, spondylosis, and osteoporosis is discussed. The hyperdigoxinemic state is seen in osteoarthritis and spondylosis and in right hemispheric dominance. The hypodigoxinemic state is seen in left hemispheric dominance and senile osteoporosis. Hemispheric dominance plays a crucial role in deciding the predisposition to bone and joint diseases. Right hemispheric chemical dominance predisposes to spondylosis and osteoarthritis. Left hemispheric chemical dominance predisposes to osteoporosis.

Topics: Digoxin; Dolichols; Dominance, Cerebral; Erythrocytes; Female; Free Radicals; Glycoconjugates; Humans; Hydroxymethylglutaryl CoA Reductases; Hypothalamus; Lysosomes; Magnesium; Male; Matched-Pair Analysis; Osteoarthritis; Osteoporosis; Sodium-Potassium-Exchanging ATPase; Spinal Osteophytosis; Ubiquinone