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Published on: June 8, 2014
A Cross-Tissue Multiomics Analysis Reveals the Protective Role of TGFBR3 in Postmenopausal Osteoporosis
Yimin Liu1, Chenxu Xie1, Kaiwen Yang1
1Clinical Medical College, North China University of Science and Technology, Tangshan, 063210, Hebei, China, ncst.edu.cn.
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.
Insights
This study identifies TGFBR3 as a novel gene protecting against postmenopausal osteoporosis (PMO). Lower TGFBR3 levels are linked to PMO, and restoring it may offer therapeutic benefits for bone health.
Area of Science:
- Genomics
- Molecular Biology
- Bone Biology
Background:
- Postmenopausal osteoporosis (PMO) arises from complex interactions between tissues.
- Current research often focuses on single tissues, limiting the discovery of systemic regulatory genes for PMO.
Purpose of the Study:
- To identify conserved genes regulating PMO by integrating human cross-tissue transcriptomic data.
- To investigate the biological functions of these genes using genetic epidemiology and experimental models.
Main Methods:
- Integrated analysis of transcriptome profiles from human blood, bone marrow, and bone tissue.
- Used differential expression analysis, gene coexpression networks, and machine learning for gene selection.
- Employed Mendelian randomization for causal inference and validated findings in an ovariectomized mouse model.
Main Results:
- Identified 97 dysregulated genes across tissues, narrowing down to 64 high-confidence candidates.
- TGFBR3 was found to be protective against PMO, with lower expression in osteoporotic mice.
- TGFBR3 expression correlated with bone density, mechanical properties, and bone remodeling markers, and was found in key bone marrow cells.
Conclusions:
- TGFBR3 is identified as a novel, cross-tissue protective regulator of postmenopausal osteoporosis.
- TGFBR3 deficiency is a key factor in PMO pathogenesis, with protective mechanisms involving osteogenic pathways and immune modulation.
