Kim Erin, Cook-Mills Joan, Morgan Gabrielle, Sredni Simone T, Pachman Lauren M
Children's Hospital of Chicago Research Center, Chicago, Illinois, USA.
Arthritis Rheum. 2012 Nov;64(11):3809-17. doi: 10.1002/art.34606.
To evaluate the effect of duration of untreated disease on vascular cell adhesion molecule 1 (VCAM-1) and microRNA (miRNA) expression in muscle biopsy samples from children with juvenile dermatomyositis (DM) as well as its effect on soluble VCAM-1 (sVCAM-1) and tumor necrosis factor α (TNFα) concentrations in sera from these children.
We enrolled 28 untreated children with juvenile DM and 8 pediatric controls. Eleven children with juvenile DM had short duration of untreated disease (symptoms for ≤2 months before muscle biopsy), and 17 had long duration of untreated disease (symptoms for >2 months before muscle biopsy). Vascular structures, characterized by immunofluorescence using antibodies against von Willebrand factor, VCAM-1, and α-smooth muscle actin, were measured for total area and intensity. Circulating sVCAM-1 and TNFα levels were determined in patients with short duration of untreated disease, patients with long duration of untreated disease, and controls. Differential expression of microRNA-126 (miR-126) in muscle biopsy samples from the 2 patient groups and the control group was detected by miRNA expression profiling and confirmed by quantitative reverse transcription-polymerase chain reaction in muscle biopsy samples from the 3 groups.
Juvenile DM patients with short duration of untreated disease had significantly higher total positive area and intensity/high power field of VCAM-1 expression than did juvenile DM patients with long duration of untreated disease (P = 0.043 and P = 0.015, respectively) or controls (P = 0.004 and P = 0.001, respectively). Von Willebrand factor antigen-positive vasculature displayed greater VCAM-1 intensity in patients with short duration of untreated disease than in patients with long duration of untreated disease (P = 0.001). Circulating levels of sVCAM-1 and TNFα were significantly higher in patients with short duration of untreated disease than in controls (P = 0.013 and P = 0.048, respectively). The miRNA miR-126, a negative regulator of VCAM-1 expression, was significantly decreased (3.39-fold; P < 0.006) in patients with short duration of untreated disease compared to controls, while miR-126 expression in patients with long duration of untreated disease did not differ significantly compared to controls.
In patients with short duration of untreated disease, miR-126 down-regulation is associated with increased VCAM-1 in both muscle and blood, suggesting that VCAM-1 plays a critical role early in juvenile DM disease pathophysiology, augmented by TNFα.
评估未治疗疾病持续时间对幼年皮肌炎（DM）患儿肌肉活检样本中血管细胞黏附分子1（VCAM-1）和微小RNA（miRNA）表达的影响，以及对这些患儿血清中可溶性VCAM-1（sVCAM-1）和肿瘤坏死因子α（TNFα）浓度的影响。
我们纳入了28例未经治疗的幼年DM患儿和8例儿科对照。11例幼年DM患儿未治疗疾病持续时间短（肌肉活检前症状持续≤2个月），17例未治疗疾病持续时间长（肌肉活检前症状持续>2个月）。使用抗血管性血友病因子、VCAM-1和α-平滑肌肌动蛋白的抗体通过免疫荧光对血管结构进行测量，以确定总面积和强度。测定未治疗疾病持续时间短的患者、未治疗疾病持续时间长的患者和对照组的循环sVCAM-1和TNFα水平。通过miRNA表达谱检测两组患者和对照组肌肉活检样本中微小RNA-126（miR-126）的差异表达，并通过定量逆转录-聚合酶链反应在三组肌肉活检样本中进行验证。
未治疗疾病持续时间短的幼年DM患者VCAM-1表达的总阳性面积和强度/高倍视野显著高于未治疗疾病持续时间长的幼年DM患者（分别为P = 0.043和P = 0.015）或对照组（分别为P = 0.004和P = 0.001）。血管性血友病因子抗原阳性血管在未治疗疾病持续时间短的患者中显示出比未治疗疾病持续时间长的患者更高的VCAM-1强度（P = 0.001）。未治疗疾病持续时间短的患者循环sVCAM-1和TNFα水平显著高于对照组（分别为P = 0.013和P = 0.048）。miR-126是VCAM-1表达的负调节因子，与对照组相比，未治疗疾病持续时间短的患者中miR-126显著降低（3.39倍；P < 0.006），而未治疗疾病持续时间长的患者中miR-126表达与对照组相比无显著差异。
在未治疗疾病持续时间短的患者中，miR-126下调与肌肉和血液中VCAM-1增加相关，提示VCAM-1在幼年DM疾病病理生理学早期起关键作用，并由TNFα增强。
