Molecular Biology Reports · Nov 4, 2026
Osteoclastogenesis associated gene signatures in postmenopausal low bone mineral density: cross-dataset transcriptomics and whole-blood validation
By Anbreen N, Iqbal MJ, Wahab H et al.
Background Osteoporosis is characterized by reduced bone mass and increased fracture risk, yet minimally invasive molecular correlates of postmenopausal low bone mineral density remain limited. Methods We independently reanalysed two human osteoclastogenesis RNA-seq datasets, GSE225974 and GSE246769, using differential-expression, Gene Ontology, KEGG, Hallmark gene set enrichment, and cross-dataset concordance analyses. Six candidate genes, LGALSL, FAXDC2, DHCR7, MYL9, RHOC, and ITGB5, were subsequently evaluated by RT-qPCR in whole blood from 100 postmenopausal women with normal bone mineral density (n=30), osteopenia (n=30), or osteoporosis (n=40). Results Across the two RNA-seq datasets, 1,782 differentially expressed genes were shared, including 1,240 concordantly upregulated and 385 concordantly downregulated genes, with strong cross-dataset effect-size correlation (r=0.74). GO and KEGG analyses identified replicated sterol/lipid, skeletal-development, adhesion/integrin, and actin-cytoskeletal programs, while Hallmark GSEA identified 22 concordantly enriched gene sets, including oxidative phosphorylation, fatty-acid metabolism, and cholesterol homeostasis. BMD was positively correlated with calcium intake and physical activity. Conversely, deteriorating bone health was positively associated with high cholesterol, low BMI, early menopause. All six candidate genes were significantly and concordantly upregulated during osteoclastogenesis in both datasets. Whole-blood RT-qPCR analysis demonstrated progressively higher relative expression across normal-BMD, osteopenia, and osteoporosis groups for all six candidates. Expression analysis from the serum validated LGALSL, RHOC, MYL9 and ITGB5 elevated expression in osteoporosis cases. Conclusion These findings identify reproducible osteoclastogenesis-associated transcriptional programs and support the six candidate genes as candidate signature correlating with the postmenopausal BMD status.