TGF-β superfamily signaling is indispensable for bone homeostasis. However, the global expression profiles of all the genes that make up this signaling module in bone and bone-related diseases have not yet been well characterized. Transcriptomic datasets from human bone marrows, bone marrow-derived mesenchymal stem cells (MSCs) and MSCs of primary osteoporotic patients were used for expression profile analyses. Protein treatments, gene quantification, reporter assay and signaling dissection in MSC lines were used to clarify the interactive regulations and feedback mechanisms between TGF-β superfamily ligands and antagonists. Ingenuity Pathway Analysis was used for network construction. We identified TGFB1 in the ligand group that carries out SMAD2/3 signaling and BMP8A, BMP8B and BMP2 in the ligand group that conducts SMAD1/5/8 signaling have relatively high expression levels in normal bone marrows and MSCs. Among 16 antagonist genes, the dominantly expressed TGF-β superfamily ligands induced only NOG, GREM1 and GREM2 via different SMAD pathways in MSCs. These induced antagonist proteins further showed distinct antagonisms to the treated ligands and thus would make up complicated negative feedback networks in bone. We further identified TGF-β superfamily signaling is enriched in MSCs of primary osteoporosis. Enhanced expression of the genes mediating TGF-β-mediated SMAD3 signaling and the genes encoding TGF-β superfamily antagonists served as significant features to osteoporosis. Our data for the first time unveiled the transcription landscape of all the genes that make up TGF-β superfamily signaling module in bone. The feedback mechanisms and regulatory network prediction of antagonists provided novel hints to treat osteoporosis.

中文翻译：

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揭示骨骼和骨质疏松症中 TGF-β 超家族信号模块的转录组学景观和潜在的拮抗剂反馈机制

TGF-β 超家族信号对于骨稳态是必不可少的。然而，构成骨骼和骨骼相关疾病中该信号模块的所有基因的全局表达谱尚未得到很好的表征。来自人类骨髓、骨髓来源的间充质干细胞 (MSC) 和原发性骨质疏松症患者的 MSC 的转录组学数据集用于表达谱分析。MSC 系中的蛋白质处理、基因定量、报告基因检测和信号分析用于阐明 TGF-β 超家族配体和拮抗剂之间的相互作用调节和反馈机制。Ingenuity Pathway Analysis用于网络构建。我们在执行 SMAD2/3 信号和 BMP8A 的配体组中鉴定了 TGFB1，进行SMAD1/5/8信号传导的配体组中的BMP8B和BMP2在正常骨髓和MSC中具有相对高的表达水平。在 16 个拮抗基因中，主要表达的 TGF-β 超家族配体通过 MSC 中的不同 SMAD 途径仅诱导 NOG、GREM1 和 GREM2。这些诱导的拮抗剂蛋白进一步显示出对处理过的配体的明显拮抗作用，因此将在骨骼中构成复杂的负反馈网络。我们进一步确定了 TGF-β 超家族信号在原发性骨质疏松症的 MSCs 中富集。介导 TGF-β 介导的 SMAD3 信号传导的基因和编码 TGF-β 超家族拮抗剂的基因表达增强是骨质疏松症的重要特征。我们的数据首次揭示了构成骨骼中 TGF-β 超家族信号模块的所有基因的转录图谱。拮抗剂的反馈机制和调控网络预测为治疗骨质疏松症提供了新的线索。