Promising Circulating MicroRNA Biomarkers

Majority of miRNAs exist and function intracellularly; however, non-tissue and cell-free circulating miRNAs are also present in extracellular compartments in all tested body fluids such as serum, plasma, synovial fluid, urine, cerebrospinal fluid, and saliva. Unlike mRNA and other nuclear acids, miRNAs in human plasma and serum are highly stable and protected from ribonuclease digestion. In addition to its stability, other distinct advantages associated with using miRNAs as biomarkers include high sensitivity, easy accessibility, and detection. Therefore, attention has been drawn to the development of circulating miRNAs as clinical biomarkers in OA [14].

In 2010, Murata et al. first investigated the presence of miR-16, miR-132, miR- 146a, miR-155, and miR-223 in plasma and synovial fluid, as well as their high stability under multiple freezing–thawing cycles [12]. They found that both synovial fluid and serum miRNAs were quite stable for storage at −20 °C and were still stable after as many as eight freeze–thawing cycles from −20 to 4 °C. The concentrations of the five miRNAs in synovial fluid were found to be much lower than those in plasma in both OA and RA patients. In addition, there was no correlation between plasma and synovial fluid miRNAs. Finally, the authors reported that the levels of miR-132 in plasma of both OA and RA were significantly reduced compared to normal [19].

Subsequently, a 3 miRNAs signature consisting of miR-454, miR-885-5p, and let-7e was identified in serum which could predict the risk of developing severe knee or hip OA. This study followed 816 individuals over a 15-year period and assessed the occurrence of severe knee or hip OA using total knee or hip arthroplasty, with at least one joint as a definitive outcome. At follow-up, 67 individuals had developed severe knee or hip OA. Screening results revealed that 12 miRNAs were differentially expressed, which were subsequently validated in the entire cohort. Validation showed that miR-454, miR-885-5p, and let-7e were strongly associated with the development of severe OA. Let-7e appeared to be the most promising biomarker to predict severe OA. Another study identified 12 differentially expressed miRNAs in the plasma of 54 patients with primary OA at early and intermediate stages (stages 2 and 3, respectively), indicating the value of these miRNAs as disease progression markers.

The origin and functions of circulating miRNAs remain largely unknown. It is widely believed that these miRNAs might be released directly from blood cells into the bloodstream or from circulating cells from damaged tissue at disease states [13].

Further studies are required to clarify the correlation of circulating miRNAs in synovial fluid to OA disease activity as well as to explore the feasibility of use circulating miRNAs as biomarkers in clinical practice.

 

Conclusion

Despite much active research into various OA biomarkers, there is no single biomarker that is sufficiently well validated and recognized to diagnose OA or aid the progression of individuals with or without OA. In a systematic review applying to the BIPED classification, van Spil and associates indicated that uCTX-II and serum COMP seem to have the best performance and promise of all commercially available OA biomarkers [6].

However, the authors commented on the current limitations of OA biomarker studies including an overall lack of consistent evidence, differences between the clinical trial populations versus population-based cohort studies, and differences in sample collection and possible publication bias. Presently, no OA biomarker is consistent to function as an OA outcome measure in clinical trials as a secondary or supportive endpoint [14].

The Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) group outlined 3 areas of future research including mechanisms of disease and development of new biomarkers, assays and technological development, and prognosis and risk. Briefly, ESCEO discussed research into the underlying mechanism of disease to validate existing biomarkers and identify new candidates, improve assays and standardize protocols that can accurately and reproducibly measure OA biomarkers in serum or urine, and identify biomarkers for early stages of OA, so treatments can be started to slow down the progression of OA [17].

Furthermore, future research advancements and refinements in genetic, proteomic, and metabolomic approaches, as well as identification and validation of panels of biomarkers that may be correlated with imaging modalities, may provide improved diagnosis, prediction, and understanding of the pathogenesis of OA. Today, there remains a need for more active research in the area of OA biomarkers [10].

 

 

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