Regulatory RNAs in rheumatology: From pathogenesis to potential therapy.

Abstract

In the past, the central dogma of molecular biology stated that after gene transcription, messenger RNAs (mRNAs) were translated to proteins with the help of ribosomal RNAs (rRNAs) and transfer RNAs (tRNAs). Recently, next-generation sequencing technology has discovered a lot of RNA transcripts that do not translate to proteins. These RNA transcripts were called non-coding RNAs (ncRNAs), initially. Then, the ncRNAs were further classified into short ncRNAs (sncRNAs) or long ncRNAs (lncRNAs) containing fewer than or more than 200 nucleotides, respectively. Among the sncRNAs, microRNAs (miRNAs) receive the most attention. The main function of miRNAs is to suppress the translation of mRNA and our previous studies showed that there are aberrantly expressed miRNAs in T cells from patients with systemic lupus erythematosus and rheumatoid arthritis, and that these miRNAs contribute to the immunopathogenesis of these diseases.1 In contrast, the functions of lncRNAs are more complex and diverse, including acting as a sponge for miRNAs, activation or inhibition of gene expression, binding to transcription factors to affect the gene expression.2 The main biologic function of these ncRNAs is to regulate the expression of genes, so it would be better to call these ncRNAs regulatory RNAs.3 In this issue, Shao et al4 showed increased serum lncRNA HOXA distal transcript antisense RNA (HOTTIP) expression levels in patients with acute gout attacks. HOTTIP has been found to be upregulated in synovial fibroblasts from patients with rheumatoid arthritis and HOTTIP could enhanced the signal transducer and activator of transcription 3 expression through miR-1908-5p.5 Shao et al4 also demonstrated that decreased HOTTIP expression significantly inhibited urate crystal-induced release of pro-inflammatory cytokines, including interleukin-1β, interleukin-8, and tumor necrosis factor-α in macrophages. Regulatory RNA is not only a very hot research topic for scientists. RNA-based therapies are now being used for treating patients. In 1998, the first RNA-based therapy approved by the US Food and Drug Administration (FDA) was fomivirsen, a synthetic antisense oligonucleotide targeting a sequence in cytomegalovirus mRNAs. In 2001, fomivirsen was withdrawn because of the availability of effective antiviral medication. Also delivering the RNAs into the target organ with sustained function was a challenge. Recently, the rapid development of mRNA-based vaccines in response to the COVID-19 pandemic has turned the tables. Now the FDA has approved a dozen RNA-based therapies for treating rare genetic disorders such as spinal muscular atrophy as well as common diseases such as hypercholesterolemia.6 Currently, precision medicine, or personalized medicine, is a hot topic. In brief, precision medicine is a novel therapeutic approach to manage a patient according to the patient's genes, and the genetic profile of the individual's tumor. However, precision medicine is still limited by the availability of the target drugs. On the other hand, RNA-based therapy might solve this issue by providing patient-customized therapy. Scientists have created an antisense oligonucleotide drug (one of the RNA-based therapies) to effectively treat a 6 year old girl diagnosed with a rare disease.7 We anticipate the application of RNA-based therapy in treating rheumatic diseases. More research should attempt to elucidate the roles of regulatory RNAs in the immunopathogenesis of rheumatic diseases. Ming-Chi Lu is an Editorial Board member of IJRD and an author of this article.