Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
MicroRNA Expression in Juvenile Dermatomyositis (JDM): Clues to Disease Pathogenesis and Chronicity.
Sredni, Simone, Hendrickson, Peter, Shrestha, Sheela, M. Pachman, Lauren
Juvenile dermatomyositis (JDM) is an autoimmune vasculopathy targeting small blood vessels. We found that: (1) untreated chronic inflammation lasting >2 mos has a strong influence on disease prognosis and molecular pathophysiology, (2) proinflammatory cytokines, IFN-a and TNF-a are increased in JDM sera and tissue damaging endothelial cells and (3) JDM patients have immune activation of VCAM-1, a soluble gatekeeper for leukocyte migration localized in high concentration on endothelial cells. It is also known that the A polymorphism of TNF-a-308 promoter region contributes to the inflammatory microenvironment in JDM, but the mechanism is not well understood. Moreover, due to absence of inflammatory process biomarkers and disease severity prognostic indicators, there are no surrogate indicators of immune activation that can guide effective treatment for JDM, as muscle enzymes normalize rapidly.
MicroRNAs (miRNAs) are non-coding RNAs usually 1825bp long that regulate several messenger RNAs simultaneously by mechanisms such as incomplete base pairing and post-transcriptional gene silencing. Modulation of levels of key miRNAs can affect regulation of several physiological and pathological functions offering a new prototype for therapeutic intervention.
After obtaining informed consent, miRNA expression profiles in diagnostic muscle biopsies (MBx) from 2 groups of children with definite/probable JDM and age/gender-matched controls were tested: (1) short duration of untreated disease (SDD), <2 mos prior to MBx; (2) long disease duration (LDD), >=2 mos of symptoms, using microarrays with locked nucleic acid technology (miRCURY LNA microRNA Array Exiqon, Vedbaek, Denmark). Selected dysregulated genes were confirmed by qRT-PCR and immunohistochemistry.
We found significant differential expression of: (1) miR-10b (p=0.03) in JDM vs. controls, (2) miR-146b (p=0.02), miR-126 (p=0.014) and miR-23a (p=0.04) when comparing SDD and LDD and (3) miR-34a (p=0.02) when comparing SDD vs LDD patients with TNF-a-308 G allele. Expression of miRNAs (23a, 126 and 146b) and of possible interactive targets (IL1B, TNF-a, VCAM-1) was verified by qRT-PCR and immunohistochemistry.
MiR-10b, down regulated in JDM vs. controls, modulates HOXD10 expression. HOXD10 controls OPN, which is important in T cell regulation/regeneration and is present in dystrophic calcifications associated with chronic cutaneous inflammation. When comparing JDM MBx of SDD vs LDD miR-23a, miR-126 and miR146b were differentially expressed. MiR-126 regulates VCAM-1 (increased in SDD) and might be a key component of vascular damage. Increase in miR-146b expression by cytokines IL-1B and TNF-a may be important in molding the phenotype of children who have had untreated chronic inflammation for a longer period.
In JDM, critical processes affecting vascular system formation/function and inflammation are modulated by miRNAs. Identification of key miRNAs will give us clues not only to JDM pathogenesis and chronicity but may reveal new potential therapeutic targets.
Supported by NIH/NIAMS R01 AR48289, Cure JM Foundation, and Macy's Miracle (LMP).
To cite this abstract, please use the following information:
Sredni, Simone, Hendrickson, Peter, Shrestha, Sheela, M. Pachman, Lauren; MicroRNA Expression in Juvenile Dermatomyositis (JDM): Clues to Disease Pathogenesis and Chronicity. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :928