miRNAs in Rheumatic Disease
Abnormal expression of miRNAs was recently reported in patients with rheumatoid arthritis (RA); a high level of miR-155 and miR-146 expression was found in synovial tissues and synovial fibroblasts isolated from patients with RA, compared with healthy controls.[41,42] The levels of both these miRNAs are also markedly upregulated in synovial fibroblasts from patients with RA following TNF/interleukin (IL)-1ß stimulation. The overexpression of miR-155 in these synovial fibroblasts reduced the expression of matrix metalloproteinase 3 (MMP-3) and impaired the induction of MMP-1 and MMP-3 by Toll-like receptor ligands and cytokines. MMPs, transmembrane proteases (various a disintegrin and metalloproteinase [ADAM] family members) and secreted ADAM with thrombospondin motifs (ADAMTS) family members are involved in the pathogenesis of RA through proteolytic activities on joint or articular cartilage. Interestingly, using the Targetscan website that predicts miRNA targets, miR-181 is predicted to target six MMPs (MMP-1, MMP-7, MMP-8, MMP-14, MMP-20, MMP-25), three ADAMs (ADAM11, ADAM21, ADAM28) and seven ADAMTSs (ADAMTS-1, ADAMTS-5, ADAMTS-6, ADAMTS-14, ADAMTS-25, ADAMTS-18, ADAMTS-19); miR-125a, miR-125b are predicted to target four MMPs (MMP-11, MMP-25, MMP-26, MMP-28), ADAM11 and ADAMTS-4. miR-155, miR-181 and miR-125 might, therefore, be involved in the modulation of destructive properties of synovial fibroblasts from patients with RA. In addition, given the fact that TNF is a key proinflammatory mediator and that miR-125b and miR-155 have opposite effects on its expression, it is possible that these two miRNAs might also be involved in RA, along with other miRNAs yet to be identified. Evidence from mouse studies indicates that mutations in the 3'-UTR of TNF transcripts have an important influence on its biosynthesis; 3'-UTR mutations can modify miRNA-TNF mRNA interactions, either by creating new or by destroying actual miRNA target sites.
The identification of candidate miRNAs that target genes implicated in rheumatic disorders, and the evaluation of the consequences of mutations in their target sites coupled to phenotypic and gene expression studies, should improve our understanding of the molecular mechanisms responsible for rheumatic disease. For example, the Su autoantigen can be coimmunoprecipitated with GW182 (an Argonaute-2-interacting protein) and Dicer antibodies, indicating that this autoantigen is part of the miRNA-processing machinery. Remarkably, anti-Su antibodies have been reported to be associated with rheumatic diseases. Future studies should address the significance of this interaction, especially its consequences on miRNA maturation. In addition, inducible costimulator (ICOS) was recently reported to be a target of miR-101. Inducible-costimulator-deficient mice are resistant to collagen-induced arthritis and develop no joint tissue inflammation. miR-101 is, therefore, another miRNA that might be implicated in RA and thus represents a novel therapeutic target.
Finally, viral infections such as Epstein-Barr virus (EBV), chronic hepatitis C virus (HCV), HIV and Kaposi's-sarcoma-associated herpes virus are frequently associated with the pathogenesis of rheumatic disorders.[48,49] There is also direct evidence for the presence of EBV in inflamed synovial cells in patients with RA.[48,49] Different reports indicate that viruses encode their own miRNAs. Viral-encoded miRNAs control the expression of viral transcripts, in addition to suppressing the host immune response during infection. Thus, miR-UL112-1 expressed by the human cytomegalovirus targets the major histocompatibility complex class 1-related chain B and, therefore, prevents the lysis of infected cells by natural killer cells. In addition, miR-K12-11, encoded by the Kaposi's-sarcoma-associated herpes virus, is orthologous to cellular miR-155 and thereby downregulates the expression of numerous similar cellular target mRNAs, potentially contributing to the increased incidence of B-cell tumors in patients infected with Kaposi's-sarcoma-associated herpes virus. It is, therefore, possible that viral-encoded miRNAs might target different host proteins, resulting in destructive inflammatory arthritis. Identifications of viral-encoded miRNAs that might be associated with the pathogenesis of rheumatic disorders represent a novel potential target for the treatment of virus-induced forms of arthritis.
Nat Clin Pract Rheumatol. 2008;4(10):534-541. © 2008 Nature Publishing Group
Cite this: MicroRNAs, The Immune System and Rheumatic Disease - Medscape - Oct 01, 2008.