Increased expression of vascular cell adhesion molecule 1 in muscle biopsy samples from juvenile dermatomyositis patients with short duration of untreated disease is regulated by miR‐126

Abstract

Objective To evaluate Juvenile Dermatomyositis (JDM) for duration of untreated disease (DUD) impact on: vascular cell adhesion molecule-1 (VCAM-1) and microRNA (miRNA) expression in muscle biopsy (MBx); soluble VCAM-1 (sVCAM-1) and TNF-α in sera. Methods Pediatric controls (n=8) and untreated JDM (n=28) enrolled. Short DUD (n=11, symptoms ≤2 months before MBx); long DUD (n=17, >2 months symptoms). Vascular structures, characterized by immunoflorescence using antibodies against von Willebrand factor (vWF), VCAM-1, and α-smooth muscle actin (SMA), were measured for total area (microns2) and intensity (pixels) (SlideBook 4.2). Circulating sVCAM-1 and TNF-α levels (Mesoscale) were determined (JDM [6 short, 8 long DUD], 5 controls). MiR-126 differential expression in JDM MBx ([3 long, 3 short DUD], 2 controls) was detected by Exiqon’s miRCURY microRNA Array, and confirmed (qRT-PCR) in JDM ([5 short, 5 long], 5 controls). Results Short DUD JDM had higher total positive area (p=0.043) and intensity/high power field, (p=0.015) of VCAM-1 expression than long DUD JDM or controls (p=0.004, p=0.001 respectively). vWF:Ag+ vasculature displayed greater VCAM-1 intensity in short DUD compared to long DUD (p=0.001). Circulating sVCAM-1 and TNF-α were higher in JDM short DUD than controls (p=0.013, p=0.048 respectively). MiR-126, a negative regulator of VCAM-1 expression, was decreased by 3.39 fold, p=0.006 in controls vs. short DUD; for controls vs. long DUD, no significant difference (0.145 fold, p=0.548). Conclusion In short DUD, miR-126 downregulation is associated with increased VCAM-1 in both muscle and blood, suggesting that VCAM-1 plays a critical role early in JDM disease pathophysiology, augmented by TNF-α.

Echocardiographic Abnormalities in New-onset Polymyositis/dermatomyositis

“…In a later study, Wang, et al found LV diastolic dysfunction frequently in DM patients without evident CV disease and reported an association between transmitral flow alteration and disease duration 11 . The longer disease duration seems to correlate with the persistent cardiomyocyte damage, pathologic calcification, and high concen-tration of the cytokines (e.g., vascular cell adhesion molecule, TNF-α), which may all contribute to the progress of the diastolic dysfunction 27 .…”

The role of microRNAs in the idiopathic inflammatory myopathies

“…Over-expression of VCAM-1 may explain the capillary abnormalities, reduced ability to regenerate microvasculature and vascular inflammation observed in JDM. A positive feedback loop of inflammation may ensue, as VCAM-1 expression returns to normal 2 months after disease onset, but inflammation continues [20].…”

“…As illustrated in Table 1 [3,8,11 && , 12-15,16 & , [17][18][19][20], an increase in miR-146b and miR-155, which are known to be associated with the innate immune response [3], has been found in three IIM miRNA studies [8,11 && ,12]. Up-regulation of miR-221 and miR-222 has been reported in both IIMs [8] and rheumatoid arthritis [13], and up-regulation of miR-21 in dermatomyositis serum [12] and in systemic lupus erythematosus (SLE) CD4þ T cells [15].…”

“…For instance, down-regulation of miR-126 results in increased levels of vascular cell adhesion molecule 1 (VCAM-1) in muscle biopsies from early untreated juvenile dermatomyositis (JDM) patients compared with controls, but not in those who had disease for more than 2 months (also untreated) [20]. VCAM-1 is expressed on active endothelial cells and is an important factor in inflammation.…”

Myositis registries and biorepositories

“…Examples include the discovery of the primary role of plasmacytoid dendritic cells and the interferon signature in the pathogenesis of dermatomyositis and JDM muscle and skin disease in several populations [40,45,46*,47,55,142,164] and that pro-inflammatory cytokines and chemokines, including TNFa and IL-6, as well as macrophage activation markers, are biomarkers of active disease [41,42,136*,143]. A role for antigen-restricted T cells in IBM [60,63*], and the pathogenesis of endothelial activation [105], muscle regeneration [106] and calcifications [107] in JDM have also been examined.…”