Challenges and promise of targeting miRNA in rheumatic diseases: a computational approach to identify miRNA association with cell types, cytokines, and disease mechanisms

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs that alter the expression of target genes at the post-transcriptional level, influencing diverse outcomes in metabolism, cell differentiation, proliferation, cell survival, and cell death. Dysregulated miRNA expression is implicated in various rheumatic conditions, including ankylosing spondylitis (AS), gout, juvenile idiopathic arthritis (JIA), osteoarthritis (OA), psoriatic arthritis, rheumatoid arthritis (RA), Sjogren’s syndrome, systemic lupus erythematosus (SLE) and systemic sclerosis. For this review, we used an open-source programming language- PowerShell, to scan the massive number of existing primary research publications on PubMed on miRNAs in these nine diseases to identify and count unique co-occurrences of individual miRNAs and the disease name. These counts were used to rank the top seven most relevant immuno-miRs based on their research volume in each rheumatic disease. Individual miRNAs were also screened for publication with the names of immune cells, cytokines, and pathological processes involved in rheumatic diseases. These occurrences were tabulated into matrices to identify hotspots for research relevance. Based on this information, we summarize the basic and clinical findings for the top three miRNAs — miR-146, miR-155, and miR-21 — whose relevance spans across multiple rheumatic diseases. Furthermore, we highlight some unique miRNAs for each disease and why some rheumatic conditions lack research in this emerging epigenetics field. With the overwhelming number of publications on miRNAs in rheumatic diseases, this review serves as a ‘relevance finder’ to guide researchers in selecting miRNAs based on the compiled existing knowledge of their involvement in disease pathogenesis. This approach applies to other disease contexts with the end goal of developing miRNA-based therapeutics.

Exosomal Osteoclast-Derived miRNA in Rheumatoid Arthritis: From Their Pathogenesis in Bone Erosion to New Therapeutic Approaches

“…Additionally, the potential therapeutic use of these molecules to impede bone erosion in patients faces various constraints. These include ensuring their effective delivery to the target tissue, understanding drug interactions, and considering patient-specific factors such as genetic and epigenetic variations, disease status, and co-morbidities [175]. Given the diverse effects that can emerge from targeting miRNAs specifically, further comprehensive research is necessary to precisely define the inhibition or overexpression of exosomal miRNAs.…”

Virus-Induced MicroRNA Modulation and Systemic Sclerosis Disease

“…These intermediates are exported by the Exportin5-RanGTP complex out of the nucleus, where a second RNase complex, consisting of the ribonuclease Dicer in association with its cofactor named “Transactivation Response element RNA-Binding Protein” (Dicer-TRBP), cleaves the pre-miRNAs into ~22 nt miRNA duplexes, generating mature miRNAs. MiRNAs are able to modulate gene expression through both cis - and trans -regulatory pathways [ 6 ]. During the cis -regulation, one of the two strands of the mature miRNA duplex is incorporated into the Argonaute (AGO) proteins (AGO1–4 in humans) to form a miRNA-induced silencing complex (miRISC), which interacts with the 3′ untranslated region (3′ UTR) of target mRNAs to induce mRNA degradation and repress gene expression at the post-transcriptional level [ 7 ].…”

“…In addition, silencing effects on gene expression have been observed in the case of miRNA interaction with 5′ UTR, coding or promoter sequences [ 8 ]. In trans -regulation, miRNAs can inhibit protein translation during the early steps of translation by interacting and/or competing with several factors: RNA-binding proteins or enzymes (e.g., decapping enzymes, deadenylase, 3′ and 5′ exonucleases, and endonucleases) involved in the 43S preinitiation complex formation or affecting post-initiation mechanisms, translation machinery, or post-translational modifiers [ 6 , 9 ].…”

“…Since their discovery, a growing body of evidence has supported their key role as epigenetic regulators of a variety of physiological processes, including cell development, proliferation, differentiation, and stress adaptation [ 14 , 15 , 16 ]. Interestingly, dysregulated miRNAs expression has been observed in pathological conditions, including several types of cancer, metabolic disorders, and cardiovascular and chronic autoimmune diseases (ADs) [ 6 , 15 ].…”

“…The diagnosis and treatment of ADs, especially of rare diseases such as SSc, are often hampered by challenges due to the complexity of the identification of initial symptoms; the poor knowledge of the disease; and the lack of rapid, accurate, and universally recognized diagnostic markers. Therefore, in recent years, growing interest has been given to the use of miRNAs as potential biomarkers or innovative therapeutic approaches [ 6 , 21 , 22 , 23 , 24 ].…”