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Bioinformatic analysis and experimental identification of blood biomarkers for chronic nonunion

慢性骨不连血液生物标志物的生物信息学分析和实验鉴定

  • 影响因子:2.05
  • DOI:10.1186/s13018-020-01735-1
  • 作者列表:"Jingwei Wu","Limin Liu","Huaijian Hu","Zhihua Gao","Shibao Lu
  • 发表时间:2020-06-07
Abstract

Abstract Background Incomplete fracture healing may lead to chronic nonunion; thus, determining fracture healing is the primary issue in the clinical treatment. However, there are no validated early diagnostic biomarkers for assessing chronic nonunion. In this study, bioinformatics analysis combined with an experimental verification strategy was used to identify blood biomarkers for chronic nonunion. Methods First, differentially expressed genes in chronic nonunion were identified by microarray data analysis. Second, Dipsaci Radix (DR), a traditional Chinese medicine for fracture treatment, was used to screen the drug target genes. Third, the drug-disease network was determined, and biomarker genes were obtained. Finally, the potential blood biomarkers were verified by ELISA and qPCR methods. Results Fifty-five patients with open long bone fractures (39 healed and 16 nonunion) were enrolled in this study, and urgent surgical debridement and the severity of soft tissue injury had a significant effect on the prognosis of fracture. After the systems pharmacology analysis, six genes, including QPCT, CA1, LDHB, MMP9, UGCG, and HCAR2, were chosen for experimental validation. We found that all six genes in peripheral blood mononuclear cells (PBMCs) and serum were differentially expressed after injury, and five genes (QPCT, CA1, MMP9, UGCG, and HCAR2) were significantly lower in nonunion patients. Further, CA1, MMP9, and QPCT were markedly increased after DR treatment. Conclusion CA1, MMP9, and QPCT are biomarkers of nonunion patients and DR treatment targets. However, HCAR2 and UGCG are biomarkers of nonunion patients but not DR treatment targets. Therefore, our findings may provide valuable information for nonunion diagnosis and DR treatment. Trial registration ISRCTN, ISRCTN13271153 . Registered 05 April 2020—Retrospectively registered.

摘要

【摘要】背景骨折不完全愈合可能导致慢性骨不连,因此,决定骨折愈合是临床治疗的首要问题。然而,没有经过验证的早期诊断生物标志物来评估慢性骨不连。本研究采用生物信息学分析结合一种实验验证策略鉴定慢性骨不连的血液生物标志物。方法首先,通过微阵列数据分析鉴定慢性骨不连中的差异表达基因。第二,用治疗骨折的中药续断 (DR) 进行药物靶基因的筛选。第三,确定了药物-疾病网络,并获得了生物标志物基因。最后,通过 ELISA 和 qPCR 方法验证了潜在的血液生物标志物。结果 55 例开放性长骨骨折患者 (39 例愈合,16 例骨不连) 入选本研究,紧急手术清创和软组织损伤的严重程度对骨折的预后有显著影响。经过系统药理学分析,选择 QPCT 、 CA1 、 LDHB 、 MMP9 、 UGCG 和 HCAR2 等 6 个基因进行实验验证。我们发现外周血单个核细胞 (PBMCs) 和血清中所有 6 个基因在损伤后均有差异表达,5 个基因 (QPCT 、 CA1 、 MMP9 、 UGCG 和 HCAR2) 骨不连患者明显较低。此外,DR 治疗后 CA1 、 MMP9 和 QPCT 显著升高。结论 CA1 、 MMP9 和 QPCT 是骨不连患者和 DR 治疗靶点的生物标志物。然而,HCAR2 和 UGCG 是骨不连患者的生物标志物,而不是 DR 治疗靶点。因此,我们的发现可能为骨不连的诊断和 DR 治疗提供有价值的信息。试用注册 ISRCTN,ISRCTN13271153。2020 年 4 月注册 05-回顾性注册。

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