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.