Transcriptome profiling identifies NETs-associated biomarkers in osteoporosis with diabetes
Background: Osteoporosis and diabetes represent major global public health challenges. Neutrophil extracellular traps (NETs) serve as key components of the innate immune system by capturing bacteria, fungi, and parasites, thereby trapping them in local environments with high concentrations of antimicrobial agents leading to their elimination. This study aimed to identify biomarkers associated with NETs in osteoporosis with diabetes, and to explore the underlying molecular mechanisms.  Methods: A transcriptomic sequencing dataset was obtained for osteoporosis combined with diabetes. The NETs-related genes (NETs-RGs) were obtained from previous literature. Biomarkers were identified through differential analysis, machine learning, and receiver operating characteristic (ROC). The identified biomarkers were further validated by qRT-PCR and ELISA. Subsequently, molecular regulatory network construction, immune infiltration analysis, enrichment analysis, and drug prediction were conducted. Results: S100A12 and SLC25A37 were identified as biomarkers. Their significant upregulation at the protein level was further confirmed by experimental validation in an independent cohort. Enrichment analysis indicated that S100A12 was significantly enriched in 68 pathways, including \"ECM receptor interaction\", \"maturity onset diabetes of the young\", and others. SLC25A37 was significantly enriched in 54 pathways, primarily including \"ribosome\", \"leishmania infection\", and \"Toll-like receptor signaling pathway\". A total of 7 immune cell types exhibited significant differences between the two groups, including neutrophils and regulatory T cells. A total of 59 miRNAs and 43 lncRNAs were predicted. Additionally, XIST-hsa-miR-146a-5p-S100A12 and XIST-hsa-miR-7-5-SLC25A37 were suggested to have potential regulatory roles in osteoporosis with diabetes. Drugs such as rimegepant and eptinezumab were associated with biomarkers. Conclusion: S100A12 and SLC25A37 were identified as biomarkers associated with NETs in osteoporosis with diabetes, providing a theoretical foundation for developing targeted treatments for osteoporosis with diabetes.