Zhao Xing-Qi, Wan Hao-Yang, He Si-Ying, Qin Han-Jun, Yu Bin, Jiang Nan
Division of Orthopaedics and Traumatology, Department of Orthopaedics, Southern Medical University Nanfang Hospital, Guangzhou, China.
Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Southern Medical University Nanfang Hospital, Guangzhou, China.
Front Physiol. 2022 Jul 25;13:808272. doi: 10.3389/fphys.2022.808272. eCollection 2022.
Previous studies had reported that () gene polymorphisms were related to the development of several inflammatory disorders. However, potential links between such variations and the risk of developing a bone infection and underlying mechanisms remain unclear. This study aimed to analyze potential associations between genetic variations and susceptibility to extremity osteomyelitis (OM) in a Chinese Han population and investigate potential mechanisms. Between January 2016 and August 2020, altogether 398 OM patients and 368 healthy controls were genotyped for six gene polymorphisms, including (rs7975232), (rs1544410), (rs2228570), (rs731236), (rs4516035), and (rs11568820) by the SNaPshot genotyping method. Then, male C57BL/6 mice were randomly divided into vitamin D-standard, -excess, -deficient, and -rescued groups. One week after making the model surgery, OM occurrence and severity were assessed using the bacterial count and histopathological staining. , phagocytosis, apoptosis, and bactericidal ability of macrophages were evaluated by overexpression or knockdown of VDR protein. Significant associations were found among rs7975232, rs1544410, and OM development by the recessive model (AA vs. AC + CC, = 0.037, OR = 0.594), homozygous model (AA vs. CC, = 0.033, OR = 0.575), and heterozygous model (CT vs. CC, = 0.049, OR = 0.610), respectively. Patients with the AA genotype of rs7975232 had a relatively higher mean level of vitamin D than those with AC and CC genotypes (22.5 vs. 20.7 vs. 19.0 ng/ml). Similarly, patients with CT genotype of rs1544410 had a relatively higher mean vitamin D level than those with CC genotype (20.94 vs. 19.89 ng/ml). Outcomes of experiments showed that the femoral bacterial load of vitamin D-deficient mice was highest among different vitamin D dose groups, with the most severe histopathological features of infection, and vitamin D supplementation partly reversed the changes. While experiment results revealed that active vitamin D promoted phagocytosis and sterilization of macrophages and inhibited apoptosis during infection. Reactive oxygen species (ROS) inhibitor inhibited apoptosis of macrophages induced by bacterial infection. Active vitamin D inhibited excessive ROS production in macrophages the VDR-Bmi1 signaling pathway. In this Chinese cohort, and are associated with a decreased risk of OM development by influencing serological vitamin D level, the latter of which reduced macrophage apoptosis with inhibition of excessive ROS production the VDR-Bmi1 signaling pathway.
先前的研究报道，（）基因多态性与多种炎症性疾病的发生有关。然而，这些变异与骨感染风险及潜在机制之间的潜在联系仍不清楚。本研究旨在分析中国汉族人群中基因变异与肢体骨髓炎（OM）易感性之间的潜在关联，并探究潜在机制。2016年1月至2020年8月期间，共对398例OM患者和368例健康对照进行了6种基因多态性的基因分型，包括（rs7975232）、（rs1544410）、（rs2228570）、（rs731236）、（rs4516035）和（rs11568820），采用SNaPshot基因分型方法。然后，将雄性C57BL/6小鼠随机分为维生素D标准组、过量组、缺乏组和挽救组。在进行模型手术后一周，通过细菌计数和组织病理学染色评估OM的发生情况和严重程度。通过VDR蛋白的过表达或敲低来评估巨噬细胞的吞噬作用、凋亡和杀菌能力。在隐性模型（AA与AC + CC相比，P = 0.037，OR = 0.594）、纯合子模型（AA与CC相比，P = 0.033，OR = 0.575）和杂合子模型（CT与CC相比，P = 0.049，OR = 0.610）中，分别发现rs7975232、rs1544410与OM发生之间存在显著关联。rs7975232基因AA基因型的患者维生素D平均水平相对高于AC和CC基因型的患者（22.5 vs. 20.7 vs. 19.0 ng/ml）。同样，rs1544410基因CT基因型的患者维生素D平均水平相对高于CC基因型的患者（20.94 vs. 19.89 ng/ml）。体内实验结果显示，在不同维生素D剂量组中，维生素D缺乏小鼠的股骨细菌载量最高，感染的组织病理学特征最严重，补充维生素D部分逆转了这些变化。而体外实验结果表明，活性维生素D促进巨噬细胞的吞噬和杀菌作用，并在感染期间抑制凋亡。活性氧（ROS）抑制剂抑制细菌感染诱导的巨噬细胞凋亡。活性维生素D通过VDR - Bmi1信号通路抑制巨噬细胞中过量ROS的产生。在这个中国队列中，和通过影响血清维生素D水平与OM发生风险降低相关，后者通过VDR - Bmi1信号通路抑制过量ROS产生从而减少巨噬细胞凋亡。
