中国组织工程研究

中国组织工程研究 ›› 2025, Vol. 29 ›› Issue (17): 3697-3704.doi: 10.12307/2025.651

• 组织构建相关数据分析 Date analysis of organization construction • 上一篇    下一篇

炎症、代谢物与骨质疏松症

吕  浩1，张  舸2，胡芷苜1，王  岩1，楚庆松1，周  瑶1，江  渟1，王久香3   

  1. 安徽中医药大学第一附属医院，1骨伤一科，3临床研究实验中心，安徽省合肥市  230031；2合肥市第三人民医院，安徽省合肥市  230031
  • 收稿日期:2024-07-17 接受日期:2024-08-15 出版日期:2025-06-18 发布日期:2024-11-07
  • 通讯作者: 江渟，主任医师，博士，博士生导师，安徽中医药大学第一附属医院骨伤一科，安徽省合肥市 230031 并列通讯作者：王久香，副研究员，博士，硕士研究生导师，安徽中医药大学第一附属医院临床研究实验中心，安徽省合肥市 230031
  • 作者简介:吕浩，男，1997年生，安徽省滁州市人，安徽中医药大学在读博士，主要从事中医药防治骨伤科疾病研究。 并列第一作者：张舸，女，1996年生，安徽省阜阳市人。
  • 基金资助:
    安徽省自然科学基金项目(面上项目)(2308085MH294)，项目负责人：江渟；安徽省重点研究与计划开发项目(202104j07020010)，项目负责人：江渟；安徽省教育厅自然科学研究(重点项目)(2022AH050510)，项目负责人：江渟

Inflammation, metabolites and osteoporosis

Lyu Hao1, Zhang Ge2, Hu Zhimu1, Wang Yan1, Chu Qingsong1, Zhou Yao1, Jiang Ting1, Wang Jiuxiang3     

  1. 1First Department of Orthopedics, 3The Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei 230031, Anhui Province, China; 2The Third People’s Hospital of Hefei, Hefei 230031, Anhui Province, China
  • Received:2024-07-17 Accepted:2024-08-15 Online:2025-06-18 Published:2024-11-07
  • Contact: Jiang Ting, MD, Chief physician, Doctoral supervisor, First Department of Orthopedics, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei 230031, Anhui Province, China Co-corresponding author: Wang Jiuxiang, MD, Associate researcher, Master’s supervisor, The Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei 230031, Anhui Province, China
  • About author:Lyu Hao, MD candidate, The First Department of Orthopedics, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei 230031, Anhui Province, China Zhang Ge, The Third People’s Hospital of Hefei, Hefei 230031, Anhui Province, China Lyu Hao and Zhang Ge contributed equally to this work.
  • Supported by:
    Anhui Provincial Natural Science Foundation (General Program), No. 2308085MH294 (to JT); the Key Research and Development Projects in Anhui Province, No. 202104j07020010 (to JT); Natural Science Research (Key Project) of Anhui Provincial Department of Education, No. 2022AH050510 (to JT)

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摘要：


文题释义：
骨质疏松症：是一种常见的骨骼疾病，其特征是骨密度降低和骨折易感性增加。骨质疏松性骨缺损的修复和再生是组织工程研究的热门。
孟德尔随机化：孟德尔随机化分析使用遗传变异作为工具变量来研究暴露因素与疾病结局之间的关系，有助于对可能存在的混杂因素影响和反向因果关系问题的解决，与传统的观察性研究相比，孟德尔随机化分析能够更精确、更可靠地进行因果推断。

背景：多项研究表明炎症、代谢物与骨质疏松症之间存在密切关系，但炎症相关蛋白与骨质疏松症之间是否存在遗传因果效应以及代谢物是否在其中发挥中介效应尚不清楚。
目的：采用孟德尔随机化方法研究了炎症相关蛋白和骨质疏松症的因果关系以及血浆代谢物在该关系中的中介作用。
方法：利用全基因组关联研究(GWAS)的汇总数据，骨质疏松症数据来fengenn数据库，炎症相关蛋白和血浆代谢物的数据来自已发表的研究。评估暴露与结局之间的关联性主要是反方差加权方法，通过双向孟德尔随机化分析探索炎症相关蛋白与骨质疏松症之间的因果关系，并通过两步孟德尔随机化分析发现潜在的发挥中介作用的血浆代谢物。随后进行敏感性分析以进一步验证结果的稳健性。采用Cochran’s Q检验评估研究结果的异质性。通过MR-egger截距法和MR-PRESSO法进行水平多效性评估。
结果与结论：①通过初步双向孟德尔随机化分析，鉴定出5种与骨质疏松症有正向因果关系且没有反向因果关系的炎症相关蛋白；其中神经鞘胚素(OR=0.895，95%CI：0.819-0.979，P=0.015)与骨质疏松症呈负相关，而趋化因子(C-X-C基序)配体1(OR=1.100，95%CI：1.002-1.209，P=0.046)。趋化因子(C-X-C基序)配体11(OR=1.150，95%CI：1.043-1.268，P=0.005)、白细胞介素17 C(OR=1.087，95%CI：1.004-1.176，P=0.040)、肿瘤坏死因子样凋亡微弱诱导因子(OR=1.108，95%CI：1.002-1.226，P=0.046)与骨质疏松症呈正相关；敏感性分析显示，这些因果效应都没有异质性和多效性。②文章还进行了两步孟德尔随机化分析发现潜在的中介血浆代谢物：1-棕榈酰gpc(16∶0)增加了神经鞘胚素对骨质疏松症的负向作用，5α-雄甾烷-3α，17β-单硫酸二醇会增加趋化因子(C-X-C基序)配体1、趋化因子(C-X-C基序)配体11介导的骨质疏松症风险性；Α-酮戊二酸与琥珀酸比值会导致趋化因子(C-X-C基序)配体11、白细胞介素17 C介导的骨质疏松症风险性增加；亚精胺、脯氨酸与反式-4-羟脯氨酸比值导致趋化因子(C-X-C基序)配体11介导的骨质疏松症风险性增加；12，13-二羟基十八碳烯酸会导致白细胞介素17 C介导的骨质疏松症风险性增加；胡椒碱代谢物C16H19NO3(3)的硫酸盐水平、腺苷3′，5′-环单磷酸腺苷会导致肿瘤坏死因子样凋亡微弱诱导因子介导的骨质疏松症风险性增加。③上述数据证实，部分炎症相关蛋白可以影响骨质疏松症的风险，这种作用是正向和负向的，并且其中一部分作用由血浆代谢物介导，这为未来探究骨质疏松症的发生发展机制提供了新的认知。

https://orcid.org/0000-0001-6758-8492(吕浩)；https://orcid.org/0009-0000-0095-2675(张舸)；
https://orcid.org/0000-0002-6847-0020(江渟)；https://orcid.org/0000-0002-3863-6587(王久香)

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

关键词: 骨质疏松症, 炎症相关蛋白, 血浆代谢物, 免疫反应, 孟德尔随机化, 因果关系, 反向因果, 双向分析, 中介效应, 全基因组关联研究

Abstract: BACKGROUND: Multiple studies and observations have indicated a close relationship between inflammation, metabolites, and osteoporosis. However, it is still unclear whether there is a genetic causal effect between inflammation-related proteins and osteoporosis and whether metabolites play a mediating role in this process.
OBJECTIVE: To investigate the causal relationships between inflammation-related proteins and osteoporosis using Mendelian randomization method as well as the mediating effect of plasma metabolites in this process.
METHODS: Summary data from genome-wide association studies (GWAS) were used, with osteoporosis data sourced from the Fengenn database, and GWAS data on inflammation-related proteins and plasma metabolites obtained from published studies. The inverse-variance weighted method was primarily used to assess the exposure-outcome relationships. Bidirectional Mendelian randomization analyses were used to explore the causal relationships between inflammation-related proteins and osteoporosis, and two-step Mendelian randomization was used to discover potential mediating metabolites. Sensitivity analyses were then performed to further validate the robustness of the results. Cochran’s Q test was used to assess heterogeneity, and horizontal pleiotropy was evaluated using the MR-Egger intercept and MR-PRESSO methods.  
RESULTS AND CONCLUSION: The initial bidirectional Mendelian randomization analysis identified five inflammation-related proteins that showed a positive causal relationship with osteoporosis and no reverse causal relationship. Artemin (odds ratio [OR]=0.895, 95% confidence interval [CI]: 0.819-0.979, P=0.015) was negatively associated with osteoporosis, whereas chemokine (C-X-C Motif) ligand 1 (OR=1.100, 95% CI: 1.002-1.209, P=0.046), chemokine (C-X-C Motif) ligand 11 (OR=1.150, 95% CI: 1.043-1.268, P=0.005), interleukin 17C (OR=1.087, 95% CI: 1.004-1.176, P=0.040), and tumor necrosis factor-like weak inducer of apoptosis (OR=1.108, 95% CI: 1.002-1.226, P=0.046) were positively associated with osteoporosis. Sensitivity analyses indicated no heterogeneity or pleiotropy in these causal effects. Subsequently, we conducted a two-step Mendelian randomization to discover potential mediating metabolites. This study showed that 1-palmitoyl-gpc (16:0) increased the negative effect of Artemin on osteoporosis. 5α-androstan-3α,17β-diol monosulfate increased the risk of osteoporosis mediated by chemokine (C-X-C Motif) ligand 1 and chemokine (C-X-C Motif) ligand 11. The ratio of α-ketoglutarate to succinate led to an increased risk of osteoporosis mediated by chemokine (C-X-C Motif) ligand 11 and interleukin-17C. Spermidine and the ratio of proline to trans-4-hydroxyproline contributed to an increased risk of osteoporosis mediated by chemokine (C-X-C Motif) ligand 11. 12,13-DiHOME contributed to an increased risk of osteoporosis mediated by interleukin-17C. The sulfate level of piperine metabolite C16H19NO3(3) and adenosine 3’,5’-cyclic monophosphate contributed to an increased risk of osteoporosis mediated by tumor necrosis factor-like weak inducer of apoptosis. In conclusion, the above data indicate that some inflammation-related proteins can influence the risk of osteoporosis, both positively and negatively, and some of these effects are mediated by plasma metabolites. This provides new insights for future investigations into the occurrence and development mechanisms of osteoporosis.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: osteoporosis, inflammation-related proteins, plasma metabolites, immune response, Mendelian randomization, causality, reverse causation, two-way analysis, mediating effect, genome-wide association studies

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