miR-let-7c-5p and miR-149-5p inhibit proinflammatory cytokine production in osteoarthritis and rheumatoid arthritis synovial fibroblasts (original) (raw)

The Role of miRNAs in Common Inflammatory Arthropathies: Osteoarthritis and Gouty Arthritis

Biomolecules, 2016

MicroRNAs (miRNAs) are small, non-coding RNA species that are highly evolutionarily conserved, from higher invertebrates to man. Up to 1000 miRNAs have been identified in human cells thus far, where they are key regulators of the expression of numerous targets at the post-transcriptional level. They are implicated in various processes, including cell differentiation, metabolism, and inflammation. An expanding list of miRNAs is known to be involved in the pathogenesis of common, non-autoimmune inflammatory diseases. Interestingly, osteoarthritis (OA) is now being conceptualized as a metabolic disease, as there is a correlation among hyperuricemia and metabolic syndrome (MetS). Experimental evidence suggests that metabolic deregulation is a commonality between these different pathological entities, and that miRNAs are key players in the modulation of metabolic routes. In light of these findings, this review discusses the role of miRNAs in OA and gouty arthritis, as well as the possible therapeutic targetability of miRNAs in these diseases.

Altered expression of microRNAs may predict therapeutic response in rheumatoid arthritis patients

International Immunopharmacology, 2020

Background: Epigenetic alternations of microRNAs (miRNAs) can contribute to the pathogenesis and progression of rheumatoid arthritis (RA). This study aimed to measure the expression level of peripheral blood miRNAs, as well as their target mRNAs, in RA patients and healthy controls (HCs), and to evaluate the potential of miRNAs as promising non-invasive biomarkers of treatment response. Methods: The peripheral expression of miRNAs, including miR-146a, miR-146b, miR-150, miR-155, miR-125a-5p, miR-223, miR-26a, and miR-21, as well as their target mRNAs, was analyzed in 90 RA patients and 30 HCs via quantitative real-time polymerase chain reaction (RT-PCR) assay. We compared differences between the patients in terms of good response (GR; n = 55) and poor response (PR; n = 35) to the conventional therapeutic approach. Results: All miRNAs were significantly overexpressed in RA patients. The expression of miR-155, miR-150, miR-146a, miR-146b, miR-125a-5p, and miR-223 increased in both groups of RA patients, compared to HCs, and miR-26a and miR-21 were the only upregulated miRNAs in the GR group versus HCs. Among the upregulated miRNAs, miR-125a-5p expression significantly changed in GR and PR patients (P = 0.047). The ROC curve analysis indicated the potential involvement of miR-125a-5p in the pathogenesis of RA. We also observed the downregulated expression of GATA3, RORC, FOXP3, TBX21, STAT1, and TRAF6 in RA patients versus HCs. Conclusion: Our findings indicated that different expression levels of miR-125a-5p in the GR and PR groups of patients may serve as a therapeutic response biomarker, which can be also used as a target for therapeutic interventions.

MiRs in RA: possible biomarkers and therapeutic targets

Arthritis Research & Therapy, 2012

After the breakthrough in the treatment of rheumatoid arthritis and numerous related disorders with biological therapies targeting TNFa at the Kennedy Institute in London Millions of patients have tremendously benefitted. However, we cannot cure these diseases yet and have to search for additional therapeutic targets. Since it was shown that synovial fibroblasts (SF) are not only effector cells responding to inflammatory stimuli, but appear endogenously activated and potentially involved into spreading the disease [1], we searched for the epigenetic modifications leading to the activated phenotype of these cells. Epigenetics in its scientific definition "is the study of all heritable and potentially reversible changes in genome function that do not alter the nucleotide sequence within the DNA", but might be considered in simpler terms as the regulation of gene expression. Epigenetic modifications include: Acetylation, Methylation, Phosphorylation, Sumoylation, miRs or microRNAs. Our laboratory is studying these processes and we have found that RASF reside in a hyperacetylated synovial tissue and appear hypomethylated [2]. Hypomethylation leads to the activated phenotype of RASF which is characterized by the production of matrix-degrading enzymes and of potent chemokines induced by Toll-like receptor signalling. Current strategies are designed to methylate these cells to deactivate and "normalise" them again. miRs are about 20 nucleotide long smallRNAs acting to destroy specific mRNA. In the race to identify specific miRs as novel targets we have identified for example, that interleukin-6 modulates the expression of the Bone Morphogenic Protein Receptor Type II through a novel STAT3microRNA cluster 17/92 pathway, which helps to explain the loss of the BMPR2 in the vascular cells in pulmonary hypertension [3]. Moreover, miR-203 is regulating the production of IL-6 [4]. Most interestingly, epigenetic therapy is also on the horizon [5]. References 1. Lefèvre S, et al: Synovial fibroblasts spread rheumatoid arthritis to unaffected joints.

Down-regulation of miR-10a-5p in synoviocytes contributes to TBX5-controlled joint inflammation

Journal of cellular and molecular medicine, 2017

MicroRNAs are considered to play critical roles in the pathogenesis of human inflammatory arthritis, including rheumatoid arthritis (RA). The purpose of this study was to determine the relationship between miR-10a-5p and TBX5 in synoviocytes and evaluate their contribution to joint inflammation. The expression of miR-10a-5p and TBX5 in the synovium of RA and human synovial sarcoma cell line SW982 stimulated by IL-1β was determined by RT-qPCR and Western blotting. The direct interaction between miR-10a-5p and TBX5 3'UTR was determined by dual-luciferase reporter assay in HeLa cells. Mimics and inhibitors of miR-10a-5p were transfected into SW982 cells. TBX5 was overexpressed by plasmid transfection or knocked down by RNAi. Proinflammatory cytokines and TLR3 and MMP13 expressions were determined by RT-qPCR and Western blotting. Down-regulated expression of miR-10a-5p and up-regulation of TBX5 in human patients with RA were found compared to patients with OA. IL-1β could reduce miR...

Prophylactic administration of miR-451 inhibitor decreases osteoarthritis severity in rats

Scientific Reports

Transfection of chondrocytes with microRNA-451(miR-451), present in growth zone cartilage of the growth plate, upregulates production of enzymes association with extracellular matrix degradation. miR-451 is also present in articular cartilage and exacerbates IL-1β effects in articular chondrocytes. Moreover, when osteoarthritis (OA) was induced in Sprague Dawley rats via bilateral anterior cruciate ligament transection (ACLT), miR-451 expression was increased in OA cartilage compared to control, suggesting its inhibition might be used to prevent or treat OA. To examine the prophylactic and therapeutic potential of inhibiting miR-451, we evaluated treatment with miR-451 power inhibitor (451-PI) at the onset of joint trauma and treatment after OA had developed. The prophylactic animal cohort received twice-weekly intra-articular injections of either 451-PI or a negative control (NC-PI) beginning on post-surgical day 3. OA was allowed to develop for 24 days in the therapeutic cohort be...

Rheumatoid Arthritis and miRNAs: A Critical Review through a Functional View

Journal of Immunology Research, 2018

Rheumatoid arthritis (RA) is a systemic autoimmune disease with severe joint inflammation and destruction associated with an inflammatory environment. The etiology behind RA remains to be elucidated; most updated concepts include the participation of environmental, proteomic, epigenetic, and genetic factors. Epigenetic is considered the missing link to explain genetic diversification among RA patients. Within epigenetic factors participating in RA, miRNAs are defined as small noncoding molecules with a length of approximately 22 nucleotides, capable of gene expression modulation, either negatively through inhibition of translation and degradation of the mRNA or positively through increasing the translation rate. Over the last decade and due to the feasibility of the identification of miRNAs among different tissues and compartments, they have been proposed as biomarkers for diagnosis, prognosis, and response to treatment in different pathologies. Nevertheless, miRNAs seem to be impor...

Role of MicroRNAs in Rheumatoid Arthritis

New Developments in the Pathogenesis of Rheumatoid Arthritis, 2017

Rheumatoid arthritis (RA) is a common autoimmune disease. The hallmarks of RA are synovial inflammation and hyperplasia, autoantibody production, systemic features, and deformity. A lot of researchers have paid attention to the possibility that microRNAs (miRNAs) play a role in the pathogenesis of RA. miRNAs are a class of small noncoding RNAs, which have 18-25 nucleotides. These small RNAs modify gene expression by binding to target messenger RNA (mRNA), and they block the translation or induce the degradation of target mRNA. Biological relevance of miRNAs has been investigated in physiological and pathological conditions. A growing body of evidence suggests that miRNAs participate in the inflammatory disorders including RA. In this chapter, an overview of biogenesis and function of miRNAs has been presented to introduce researchers to the changes and functional regulation of the key miRNAs in RA and to provide current knowledge in miRNA and RA. It is important to understand the relationship between the key miRNAs and RA pathology as modulation of specific miRNA alterations could be of great pharmaceutical interest in the future.