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Bioinformatic analysis and experimental identification of blood biomarkers for chronic nonunion


  • 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 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】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。



作者列表:["Zhang X","Ehrlich KC","Yu F","Hu X","Meng XH","Deng HW","Shen H","Ehrlich M"]

METHODS::A major challenge in translating findings from genome-wide association studies (GWAS) to biological mechanisms is pinpointing functional variants because only a very small percentage of variants associated with a given trait actually impact the trait. We used an extensive epigenetics, transcriptomics, and genetics analysis of the TBX15/WARS2 neighbourhood to prioritize this region's best-candidate causal variants for the genetic risk of osteoporosis (estimated bone density, eBMD) and obesity (waist-hip ratio or waist circumference adjusted for body mass index). TBX15 encodes a transcription factor that is important in bone development and adipose biology. Manual curation of 692 GWAS-derived variants gave eight strong candidates for causal SNPs that modulate TBX15 transcription in subcutaneous adipose tissue (SAT) or osteoblasts, which highly and specifically express this gene. None of these SNPs were prioritized by Bayesian fine-mapping. The eight regulatory causal SNPs were in enhancer or promoter chromatin seen preferentially in SAT or osteoblasts at TBX15 intron-1 or upstream. They overlap strongly predicted, allele-specific transcription factor binding sites. Our analysis suggests that these SNPs act independently of two missense SNPs in TBX15. Remarkably, five of the regulatory SNPs were associated with eBMD and obesity and had the same trait-increasing allele for both. We found that WARS2 obesity-related SNPs can be ascribed to high linkage disequilibrium with TBX15 intron-1 SNPs. Our findings from GWAS index, proxy, and imputed SNPs suggest that a few SNPs, including three in a 0.7-kb cluster, act as causal regulatory variants to fine-tune TBX15 expression and, thereby, affect both obesity and osteoporosis risk.

作者列表:["Riffel P","Schwaab J","Lutz C","Naumann N","Metzgeroth G","Fabarius A","Schoenberg SO","Hofmann WK","Valent P","Reiter A","Jawhar M"]

METHODS:PURPOSE:Systemic mastocytosis (SM) is characterized by the expansion of clonal mast cells that infiltrate various organ systems. The extent of organ infiltration and subsequent organ damage distinguishes between indolent SM (ISM) defined by a nearly normal life expectancy and advanced SM (AdvSM) defined by poor prognosis. In ISM, measurement of the bone mineral density (BMD) frequently reveals osteoporosis. In contrast, the clinical implication of an increased BMD and osteosclerosis remains unclear. METHODS:BMD was evaluated in 61 patients with mastocytosis (ISM, n = 29, 48%; AdvSM, n = 32, 52%). We correlated the prevalence of osteoporosis, increased BMD and osteosclerosis with clinical parameters, disease variant and prognosis. RESULTS:Osteoporosis was detected in 11/29 (38%) patients with ISM but only in 2/32 (6%) patients with AdvSM (p = 0.004). An increased BMD was detected in 1/29 (3%) patients with ISM and 24/32 (75%) patients with AdvSM (p < 0.001) while osteosclerosis was only detected in AdvSM patients (16/32, 50%). AdvSM patients with increased BMD had higher levels of bone marrow mast cell infiltration, higher serum tryptase and alkaline phosphatase levels compared to ISM as well as higher number of high-molecular risk mutations (p < 0.05). In addition, we found that the prognosis of AdvSM patients with increased BMD is inferior compared to those without increased BMD (median overall survival 3.6 years versus not reached, p = 0.031). CONCLUSIONS:Osteoporosis is a common feature in ISM but not in AdvSM. An increased BMD is frequently present in AdvSM but not in ISM and is associated with more advanced disease and inferior outcome.

作者列表:["Kotak DJ","Devarajan PV"]

METHODS::We present salmon calcitonin (SCT) loaded Hydroxyapatite nanoparticles (HAP-NPs) for sublingual osteoporosis therapy. Surface stabilized HAP-NPs were prepared by aqueous precipitation. SCT was loaded by ionic complexation, as confirmed by FTIR. SCT-HAP-NPs exhibited high loading efficiency (~85%), average size (~100nm), and zeta potential (~-25 mv). Stability of SCT was established by circular dichroism spectroscopy and HPLC analysis. Confocal laser scanning microscopy confirmed deep penetration of SCT-HAP-NPs into the mucosa with >4-fold enhancement in permeability relative to SCT solution. Sublingual SCT-HAP-NPs revealed relative bioavailability of ~15% compared to the subcutaneous injection in rabbits (200iu). Significant and comparable improvement in serum biomarkers with increase in bone mass and mechanical strength and decreased bone erosion compared to subcutaneous SCT was confirmed in ovariectomized (OVX) osteoporosis rat model. Such comparable pharmacodynamic effect at the same dose suggested targeted bone delivery and promise of sublingual SCT-HAP-NPs as a non-invasive alternative to the injection.