Targeting dysregulated glycolysis in type 2 diabetic osteoporosis: Identification of a diagnostic gene signature and therapeutic validation of calcifediol
Abstract
Type 2 diabetic osteoporosis (T2DOP) is a significant complication of type 2 diabetes, characterized by an increased risk of fractures. While dysregulated bone cell glucose metabolism is implicated, its specific mechanisms are unclear. This research combined bioinformatics with experimental validation to examine glycolysis-related genes in T2DOP. We merged osteoporosis and type 2 diabetes datasets, then applied differential expression analysis, WGCNA, and machine learning (113 algorithms) to identify core biomarkers. Functional enrichment, immune infiltration, and scRNA-seq analyses elucidated their roles. L1000FWD screened potential drugs, validated by molecular docking and in a T2D mouse model. We identified eight key biomarkers (ATN1, PDLIM7, PLD3, ACADSB, PDZK1, RAPGEF4, MYBPC3, BSG) with high diagnostic value (AUC > 0.75). They were enriched in glucose metabolism and osteoclast pathways. Immune analysis revealed altered infiltration, and scRNA-seq indicated their primary influence on osteoblasts, mesenchymal stem cells, and osteoclasts. Calcifediol (25(OH)D₃) was the top drug candidate, showing strong binding affinity. In vivo, 25(OH)D₃ treatment ameliorated bone loss, improved metabolic parameters, and modulated key biomarker expression. Our research identifies eight glycolysis-related genes as candidate diagnostic and therapeutic targets with biological and causal plausibility for T2DOP. Calcifediol demonstrates promise as a preclinical therapeutic candidate for…
Read the paper
Related studies
- Effectiveness of Bisphosphonates and Denosumab on Risk of Vertebral Fractures in Prostate Cancer Patients Under Androgen Deprivation Therapies: A Real-World Prospective Study
- Osteoporosis-related fractures after spinal cord injury: a retrospective study from Brazil
- Serum 25-hydroxyvitamin D, parathyroid hormone, and mortality in older men
- Lack of Association between Vitamin D Insufficiency and Cardiovascular or Fracture Risk: A UK Biobank Study
- Muscle strength and body composition are clinical indicators of osteoporosis
- Incidence of bone protection and associated fragility injuries in patients with proximal femur fractures
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.