Plasma and synovial fluid microRNAs as potential biomarkers of rheumatoid arthritis and osteoarthritis

Abstract

IntroductionMicroRNAs (miRNAs), endogenous small noncoding RNAs regulating the activities of target mRNAs and cellular processes, are present in human plasma in a stable form. In this study, we investigated whether miRNAs are also stably present in synovial fluids and whether plasma and synovial fluid miRNAs could be biomarkers of rheumatoid arthritis (RA) and osteoarthritis (OA).MethodsWe measured concentrations of miR-16, miR-132, miR-146a, miR-155 and miR-223 in synovial fluid from patients with RA and OA, and those in plasma from RA, OA and healthy controls (HCs) by quantitative reverse transcription-polymerase chain reaction. Furthermore, miRNAs in the conditioned medium of synovial tissues, monolayer fibroblast-like synoviocytes, and mononuclear cells were examined. Correlations between miRNAs and biomarkers or disease activities of RA were statistically examined.ResultsSynovial fluid miRNAs were present and as stable as plasma miRNAs for storage at -20°C and freeze-thawing from -20°C to 4°C. In RA and OA, synovial fluid concentrations of miR-16, miR-132, miR-146a, and miR-223 were significantly lower than their plasma concentrations, and there were no correlation between plasma and synovial fluid miRNAs. Interestingly, synovial tissues, fibroblast-like synoviocytes, and mononuclear cells secreted miRNAs in distinct patterns. The expression patterns of miRNAs in synovial fluid of OA were similar to miRNAs secreted by synovial tissues. Synovial fluid miRNAs of RA were likely to originate from synovial tissues and infiltrating cells. Plasma miR-132 of HC was significantly higher than that of RA or OA with high diagnosability. Synovial fluid concentrations of miR-16, miR-146a miR-155 and miR-223 of RA were significantly higher than those of OA. Plasma miRNAs or ratio of synovial fluid miRNAs to plasma miRNAs, including miR-16 and miR-146a, significantly correlated with tender joint counts and 28-joint Disease Activity Score.ConclusionsPlasma miRNAs had distinct patterns from synovial fluid miRNAs, which appeared to originate from synovial tissue. Plasma miR-132 well differentiated HCs from patients with RA or OA, while synovial fluid miRNAs differentiated RA and OA. Furthermore, plasma miRNAs correlated with the disease activities of RA. Thus, synovial fluid and plasma miRNAs have potential as diagnostic biomarkers for RA and OA and as a tool for the analysis of their pathogenesis.

Evidence that miR‐146a attenuates aging‐ and trauma‐induced osteoarthritis by inhibiting Notch1, IL‐6, and IL‐1 mediated catabolism

“…Recent studies have revealed that miR‐146 is primarily involved in the regulation of inflammation and other processes that function in the innate immune system (Sonkoly, Stahle & Pivarcsi, 2008). miR‐146a has been shown to be a circulating miRNA that is increased in synovial tissues and fibroblasts in rheumatoid arthritis (RA) patients as a particularly important negative regulator of nuclear factor‐κB (NF‐κB) signaling (Murata et al., 2010; Stanczyk et al., 2008; Taganov, Boldin, Chang & Baltimore, 2006). miR‐146a has also received much attention in the field of OA research.…”

MicroRNA‐132 suppresses autoimmune encephalomyelitis by inducing cholinergic anti‐inflammation: A new Ahr‐based exploration

“…The role of miR-132 in inflammation and autoimmunity is not well established. MiR-132 is differentially expressed in different tissues and in the synovial fluid from rheumatoid arthritis patients [16,17]. However, no further studies have investigated the importance of these miRNA to autoimmunity.…”

The Role of miRNA in Rheumatoid Arthritis

“…In culture, RA fibroblast like synoviocytes (FLS) proliferate and secrete a variety of cytokines/ chemokines/angiogenic factors, including fibroblast growth factor, granulocytemacrophage colony stimulating factor, interleukin 6 (IL-6), IL-8, monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory proteins 1 , and they present various adhesion molecules on their surfaces. Since the first report by Stanczyk et al in 2008, several reports have described the altered miRNAs in the joint and/or peripheral blood leucocytes of patients with RA, including miR-155, miR-146 and others (Table 1) ( Stanczyk, et al, 2008;Nakasa, et al, 2008;Pauley, et al, 2008;Murata, et al, 2010;Li, et al, 2010;Fulci, et al, 2010;Nakamachi, et al, 2009. Niimoto, et al, 2010.…”