Balancing osteogenesis and adipogenesis in osteogenesis imperfecta: PLIN2 and E2F2 as key targets for mesenchymal stem cell therapy

BACKGROUND: Osteogenesis imperfecta (OI) necessitates innovative mesenchymal stem cell (MSC) therapies targeting key molecular pathways to enhance targeted and combination treatments and improve bone health. OBJECTIVES: To investigate the therapeutic mechanisms of various interventions for OI by analyzing relevant datasets, with a focus on lipid metabolism-related genes, particularly PLIN2, in order to determine whether they influence the balance between osteoblast and adipocyte differentiation. MATERIAL AND METHODS: This study analyzed datasets from the Gene Expression Omnibus (GEO; GSE157587, GSE214064, GSE186141) and UK Biobank genome-wide association study (GWAS) summary statistics (UKB-b-4657, UKB-b-1096, UKB-b-8875, UKB-b-20124) using bioinformatics tools, including GEO2R, DESeq2, TwoSampleMR, MR-Egger, MR-PRESSO, gwasrapidd, and summary data-based Mendelian randomization (MR), to identify differentially expressed genes (DEGs) and assess causal relationships with heel bone mineral density (BMD). RESULTS: Differentially expressed genes analysis of GSE157587 identified PLIN2 as the most significant gene influenced by MSC therapy in OI (log2 fold change = 0.428, adjusted p = 3.29 × 10-6), whereas GSE186141 revealed 770 DEGs in OI patients, with 7 overlapping with PLIN2-related genes. Notably, TNFRSF19 (log2 fold change = -2.7454, adjusted p = 3.930 × 10-7 in OI; 1.5001, adjusted p = 3.482 × 10-3 in PLIN2 knockdown) and E2F2 (log2 fold change = -2.1428, adjusted p = 8.830 × 10-5 in OI; 1.7207, adjusted p = 1.244 × 10-2 in PLIN2 knockdown) were identified as key genes. Mendelian randomization analysis confirmed a negative association between E2F2 and heel BMD (p = 1.116 × 10-7 to 6.073 × 10-5; effect size -0.0461 to -0.0277). CONCLUSIONS: PLIN2 and E2F2 emerge as critical targets for refining MSC therapy in OI, with the potential to improve bone formation and reduce fat accumulation by restoring the osteogenesis-adipogenesis balance. These findings may support the development of combination therapies or engineered MSCs, ultimately improving clinical outcomes for patients with OI.