Identification of Key Osteoporosis Genes Through Comparative Analysis of Men's and Women's Osteoblast Transcriptomes

Abstract

Osteoporosis disproportionately affects older women, yet gender differences in human osteoblasts remain unexplored. Identifying mechanisms and biomarkers of osteoporosis will enable the development of preventative and therapeutic approaches. Transcriptome data of 187 osteoblast samples from men and women were compared. Differentially expressed genes (DEGs) were identified, and weighted gene co-expression network analysis (WGCNA) was used to discover co-expressed modules. Enrichment analysis was performed to annotate DEGs. Preservation analysis determined whether modules and pathways were similar between genders. Blood methylation, transcriptome data, mouse phenotype data, and drug treatment data were utilized to identify key osteoporosis genes. We identified 1460 DEGs enriched in immune response, neurogenesis, and GWAS osteoporosis-related genes. WGCNA uncovered 8 modules associated with immune response, development, collagen metabolism, mitochondrion, and amino acid synthesis. Preservation analysis indicated modules and pathways were generally similar between genders. Incorporating GWAS and mouse phenotype data revealed 9 key genes, including GMDS, SMOC2, SASH1, MMP2, AHCYL1, ARRDC2, IGHMBP2, ATP6V1A, and CTSK. These genes were differentially methylated in patient blood and differentiated high and low bone mineral density patients in pre- and postmenopausal women. Denosumab treatment in postmenopausal women down-regulated 6 key genes, up-regulated T cell proportions, and down-regulated fibroblast proportion. qRT-PCR was used to confirm the genes in postmenopausal women. We identified 9 key osteoporosis genes by comparing the transcriptome of osteoblasts in women and men. Our findings' clinical implications were confirmed by multi-omics data and qRT-PCR, and our study provides novel biomarkers and therapeutic targets for osteoporosis diagnosis and treatment.

Keywords: ATP6V1A; Bone mineral density; CTSK; Epigenetic; Fracture.