Causal association analysis between blood metabolomes and osteopenia and therapeutic target prediction for mechanomedicine

Ruobing Liu , Yaru Huang , Maogang Jiang , Fei Xu , Qilin Pei , Jiajun Ma , Youru Li , Siqi Shen , Bo Zhang , Xiangyang Guo , Jing Cai , Wenwen Wang
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Abstract

Blood metabolomes have been linked to osteoporosis, yet the precise causal relationship with osteopenia, its preventable early stage, remains unclear. This study aimed to uncover the genetic causality between blood metabolomes and osteopenia, pinpointing potential targets for mechanomedicine. Utilizing genome-wide association study summary statistics, we analyzed 1091 metabolites and 309 metabolite ratios from 8299 individuals, correlating them with total body bone mineral density (BMD) from 56,284 individuals in the IEU GWAS database and osteopenia data from 408,961 European populations. Through two-sample Mendelian randomization, we investigated the association between blood metabolomes and skeletal characteristics. We then conducted summary-data-based Mendelian randomization (MR) analysis and colocalization analyses to identify causal genes related to skeletal phenotypes, predicting therapeutic targets for osteopenia. Expression of potential targets in osteocytes under fluid shear stress (FSS) stimulation was tested using qRT-PCR to explore mechanical sensitivity and bone health mechanisms. Our findings revealed five metabolites affecting total body BMD and osteopenia, with biliverdin emerging as a potential protective factor against osteopenia (OR ​= ​0.93, 95 ​%CI ​= ​0.88–0.98, P ​= ​0.009). Additionally, three genes—LRRC14, SLC22A16, and TNFRSF1A—were identified as potential therapeutic targets for osteopenia. Notably, LRRC14 and TNFRSF1A are also associated with other musculoskeletal diseases. In vitro experiments showed that FSS significantly increased LRRC14 expression in osteocytes, suggesting its potential as a mechanosensitive factor. This study identifies candidate blood metabolites and mechanomedicine targets for osteopenia, offering a scientific basis for new diagnostic and treatment strategies and deepening our understanding of bone mechanics response characteristics.

Abstract Image

血液代谢组学与骨质减少的因果关系分析及机械药物治疗靶点预测
血液代谢组与骨质疏松症有关,但与骨质减少的确切因果关系,其可预防的早期阶段,仍不清楚。本研究旨在揭示血液代谢组与骨质减少之间的遗传因果关系,确定机械医学的潜在靶点。利用全基因组关联研究汇总统计,我们分析了8299名个体的1091种代谢物和309种代谢物比率,并将它们与IEU GWAS数据库中56,284名个体的总体骨密度(BMD)和408,961名欧洲人群的骨质减少数据进行了关联。通过双样本孟德尔随机化,我们研究了血液代谢组与骨骼特征之间的关系。然后,我们进行了基于汇总数据的孟德尔随机化(MR)分析和共定位分析,以确定与骨骼表型相关的致病基因,预测骨质减少的治疗靶点。利用qRT-PCR技术检测了在流体剪切应力(FSS)刺激下骨细胞中潜在靶点的表达,以探索机械敏感性和骨健康机制。我们的研究结果显示,有5种代谢物影响全身骨密度和骨质减少,其中胆绿素是预防骨质减少的潜在保护因子(OR = 0.93, 95% CI = 0.88-0.98, P = 0.009)。此外,三个基因lrrc14、SLC22A16和tnfrsf1a被确定为骨质减少的潜在治疗靶点。值得注意的是,LRRC14和TNFRSF1A也与其他肌肉骨骼疾病相关。体外实验表明,FSS显著增加了LRRC14在骨细胞中的表达,提示其可能是一种机械敏感因子。本研究确定了骨减少的候选血液代谢物和机械药物靶点,为新的诊断和治疗策略提供了科学依据,加深了我们对骨力学反应特征的理解。
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