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靶向TYROBP以影响间充质干细胞的免疫微环境和成骨分化。

Targeting TYROBP to influence the immune microenvironment and osteogenic differentiation of mesenchymal stem cells.

作者信息

Huang Liangkun, Pei Zijie, Zhang Tongyi, Zhang Ze, Sun Fengpo, Wen Liangyuan

机构信息

Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China.

出版信息

J Orthop Surg Res. 2025 May 28;20(1):535. doi: 10.1186/s13018-025-05925-7.

DOI:10.1186/s13018-025-05925-7
PMID:40437576
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12117746/
Abstract

BACKGROUND: Lactate, as an end product of glycolysis, plays an important role in cellular metabolism and signal transduction, and recent studies have shown that it is closely related to cellular differentiation, but its potential role in osteogenic differentiation has not yet been fully investigated. METHODS: We obtained two datasets containing human mesenchymal stem cells and human osteoblasts, GSE12266 and GSE18043, from the GEO database, which contained a total of 14 samples with sequencing data, and searched for lactate metabolism-related genes from the Genecards database. Ten differentially expressed core genes related to lactate metabolism were identified by differential expression analysis, protein interaction network analysis, and correlation expression analysis, and determined to play a key role in osteogenic differentiation. The effects of hub genes on the immune microenvironment of osteogenic differentiation were explored by enrichment analysis and immune infiltration analysis, and the significant effects of the key gene TYRO Protein Tyrosine Kinase-Binding Protein(TYROBP) on the characterization of bone marrow mesenchymal stem cells (BMSCs) were experimentally verified, and it was determined by drug sensitivity analysis that TYROBP may be a regulatory target of certain drugs affecting osteogenic differentiation. RESULT: We successfully screened 10 differentially expressed hub genes related to lactate metabolism, and their area under the curve AUC values for predicting osteogenic differentiation were all highly favorable. Enrichment analysis showed that lactate metabolism may affect osteoblast differentiation through immune infiltration, and the immune infiltration results confirmed the strong association between hub genes and osteoblast immune infiltration status. It was verified that decreasing TYROBP expression promoted cell viability, proliferation and migration ability of BMSCs. Drug sensitivity analysis showed that TYROBP may be a major regulator of drug-induced MSC differentiation. CONCLUSION: Our study reveals the critical role of lactate metabolism in osteoblast differentiation, identifies the role of the key gene TYROBP in the regulation of BMSCs, and provides new insights for studies related to the regulation of osteoblast differentiation.

摘要

背景：乳酸作为糖酵解的终产物，在细胞代谢和信号转导中发挥重要作用，近期研究表明其与细胞分化密切相关，但其在成骨分化中的潜在作用尚未得到充分研究。 方法：我们从基因表达综合数据库（GEO数据库）中获取了两个包含人间充质干细胞和人成骨细胞的数据集GSE12266和GSE18043，其中共有14个带有测序数据的样本，并从基因卡片数据库中搜索与乳酸代谢相关的基因。通过差异表达分析、蛋白质相互作用网络分析和相关性表达分析，确定了10个与乳酸代谢相关的差异表达核心基因，它们在成骨分化中起关键作用。通过富集分析和免疫浸润分析探讨了枢纽基因对成骨分化免疫微环境的影响，并通过实验验证了关键基因酪氨酸蛋白酪氨酸激酶结合蛋白（TYROBP）对骨髓间充质干细胞（BMSC）特性的显著影响，通过药物敏感性分析确定TYROBP可能是某些影响成骨分化药物的调控靶点。 结果：我们成功筛选出10个与乳酸代谢相关的差异表达枢纽基因，它们预测成骨分化的曲线下面积（AUC）值都非常理想。富集分析表明，乳酸代谢可能通过免疫浸润影响成骨细胞分化，免疫浸润结果证实了枢纽基因与成骨细胞免疫浸润状态之间的强关联。证实降低TYROBP表达可促进BMSC的细胞活力、增殖和迁移能力。药物敏感性分析表明，TYROBP可能是药物诱导的间充质干细胞分化的主要调节因子。 结论：我们的研究揭示了乳酸代谢在成骨细胞分化中的关键作用，确定了关键基因TYROBP在BMSC调控中的作用，并为成骨细胞分化调控相关研究提供了新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9aed/12117746/ab01624f86a2/13018_2025_5925_Fig13_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9aed/12117746/b843d81a7956/13018_2025_5925_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9aed/12117746/a6ec2d565cbb/13018_2025_5925_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9aed/12117746/c0a9b8ce6dd3/13018_2025_5925_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9aed/12117746/a8d03fdddea4/13018_2025_5925_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9aed/12117746/c17b7a223b25/13018_2025_5925_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9aed/12117746/91e9f80b1c2f/13018_2025_5925_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9aed/12117746/d37b7f88248a/13018_2025_5925_Fig11_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9aed/12117746/5af2fdcd9a88/13018_2025_5925_Fig12_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9aed/12117746/ab01624f86a2/13018_2025_5925_Fig13_HTML.jpg

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