A Cross‐Tissue Multiomics Analysis Reveals the Protective Role of TGFBR3 in Postmenopausal Osteoporosis

Background Postmenopausal osteoporosis (PMO) develops as a result of pathological cross‐tissue interactions. However, current experimental paradigms are constrained by their single‐tissue focus, hindering efforts to discover systemwide regulatory genes. Objective We aimed to discover conserved genetic regulators of PMO by integrating cross‐tissue transcriptomic profiles in humans and to characterize their biological functions via combined genetic epidemiology and experimental studies using integrated analytical strategies. Methods Our analytical framework encompassed transcriptome profiles from human peripheral blood mononuclear cells, bone marrow, and bone tissue. We adopted a tiered strategy involving differential expression analysis, weighted gene coexpression network construction, and machine learning with 108 algorithm combinations for candidate gene selection. A two‐sample Mendelian randomization was used to inform causal gene–disease relationships, while the key results were validated in an ovariectomized mouse model of osteoporosis. Mechanistic studies included single‐cell transcriptomics, functional enrichment, and immune microenvironment profiling. Results Cross‐tissue analysis identified 97 consistently dysregulated genes between tissues, which were further refined to 64 high‐confidence candidates. TGFBR3 was significantly protective against PMO (IVW OR = 0.675, 95% CI: 0.466–0.977, p = 0.037). Osteoporotic mice exhibited considerable downregulation of TGFBR3 expression, which was positively correlated with bone mineral density and mechanical properties as well as bone formation markers and negatively correlated with resorption markers. Cellular localization showed enrichment of TGFBR3 in bone marrow mesenchymal stem cells and T cells from human and mouse bone marrow. Functional analyses suggested that its protective effects involve the modulation of osteogenic differentiation pathways and regulation of the immune microenvironment. Conclusion This is the first study to identify TGFBR3 as a novel cross‐tissue protective regulator of PMO. Our integrated approach covering genomic discovery, causal inference, and experimental validation offers strong support to the hypothesis that TGFBR3 deficiency constitutes a fundamental feature of PMO pathogenesis, while shedding light on its multilevel protective mechanisms.