Sequencing identifies a distinct signature of circulating microRNAs in early radiographic knee osteoarthritis

Ali, Shabana Amanda; Gandhi, Rajiv; Potla, P.; Keshavarzi, Sareh; Espin‐Garcia, Osvaldo; Shestopaloff, Konstantin; Pastrello, Chiara; Bethune-Waddell, Dylan; Lively, Starlee; Perruccio, Anthony V.; Rampersaud, Y. Raja; Veillette, Christian; Rockel, Jason S.; Jurišica, Igor; Appleton, T.; Kapoor, Mohit

doi:10.1016/j.joca.2020.07.003

Cited by 48 publications

(47 citation statements)

References 45 publications

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“…Approaching the whole organ might be less sensitive in detecting gene alterations in single tissues and might limit the ability to determine which particular tissue contributed to expression of a specific gene, however it has the advantage of allowing discovery of genes more globally involved in OA progression. A total of 763 microRNAs across all libraries were identified; similar numbers of microRNAs have been identified in previous studies [ 30 , 31 ]. Differences in joint microRNA profiles could be correlated to the animals’ disease state and/or age, with a total of 19 microRNAs DE between young and old; Sham and DMM; and old and DMM.…”

Section: Discussionsupporting

confidence: 52%

Mouse microRNA signatures in joint ageing and post-traumatic osteoarthritis

Castanheira

Anderson

Fang

et al. 2021

Osteoarthritis and Cartilage Open

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Objective This study investigated mice serum and joint microRNA expression profiles in ageing and osteoarthritis to elucidate the role of microRNAs in the development and progression of disease, and provide biomarkers for ageing and osteoarthritis. Design Whole joints and serum samples were collected from C57BL6/J male mice and subjected to small RNA sequencing. Groups used included; surgically-induced post-traumatic osteoarthritis, (DMM; 24 months-old); sham surgery (24 months-old); old mice (18 months-old); and young mice (8 months-old). Differentially expressed microRNAs between the four groups were identified and validated using real-time quantitative PCR. MicroRNA differential expression data was used for target prediction and pathway analysis. Results In joint tissues, miR-140–5p, miR-205–5p, miR-682, miR-208b-3p, miR-499–5p, miR-455–3p and miR-6238 were differentially expressed between young and old groups; miR-146a-5p, miR-3474, miR-615–3p and miR-151–5p were differentially expressed between DMM and Sham groups; and miR-652–3p, miR-23b-3p, miR-708–5p, miR-5099, miR-23a-3p, miR-214–3p, miR-6238 and miR-148–3p between the old and DMM groups. The number of differentially expressed microRNAs in serum was higher, some in common with joint tissues including miR-140–5p and miR-455–3p between young and old groups; and miR-23b-3p, miR-5099 and miR-6238 between old and DMM groups. We confirmed miR-140–5p, miR-499–5p and miR-455–3p expression to be decreased in old mouse joints compared to young, suggesting their potential use as biomarkers of joint ageing in mice. Conclusions MiR-140–5p, miR-499–5p and miR-455–3p could be used as joint ageing biomarkers in mice. Further research into these specific molecules in human tissues is now warranted to check their potential suitability as human biomarkers of ageing.

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Section: Discussionsupporting

confidence: 52%

Mouse microRNA signatures in joint ageing and post-traumatic osteoarthritis

Castanheira

Anderson

Fang

et al. 2021

Osteoarthritis and Cartilage Open

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“…Common miRNAs between OA-EVs and H-EVs that were not present in OA-MSCs included previously noted miR-142-3p and miR-630 [ 86 ] that have been described as “cartilage-protective.” Also miR-29a-3p was described as protective for cartilage [ 86 ]. Healthy EVs higher-expressed miR-145-5p (uniquely highly expressed in H-EVs compared to OA-EVs) described as having a dual role in OA [ 90 ], while OA-EVs higher-expressed hsa-miR-199a-5p involved in chondrogenesis regulation and bone formation [ 91 ], as well as highly expressed in OA SF EVs [ 57 ] and in plasma of early OA patients [ 92 ]. Our in vitro data have revealed that both H-EVs and OA-EVs marginally but significantly improved the viability of OA chondrocytes, with no difference to each other, which could be a result of consorted activity of multiple miRNAs.…”

Section: Discussionmentioning

confidence: 99%

Characterization and miRNA Profiling of Extracellular Vesicles from Human Osteoarthritic Subchondral Bone Multipotential Stromal Cells (MSCs)

Sanjurjo‐Rodríguez

Crossland

Reis

et al. 2021

Stem Cells International

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Osteoarthritis (OA) is a heterogeneous disease in which the cross-talk between the cells from different tissues within the joint is affected as the disease progresses. Extracellular vesicles (EVs) are known to have a crucial role in cell-cell communication by means of cargo transfer. Subchondral bone (SB) resident cells and its microenvironment are increasingly recognised to have a major role in OA pathogenesis. The aim of this study was to investigate the EV production from OA SB mesenchymal stromal cells (MSCs) and their possible influence on OA chondrocytes. Small EVs were isolated from OA-MSCs, characterized and cocultured with chondrocytes for viability and gene expression analysis, and compared to small EVs from MSCs of healthy donors (H-EVs). OA-EVs enhanced viability of chondrocytes and the expression of chondrogenesis-related genes, although the effect was marginally lower compared to that of the H-EVs. miRNA profiling followed by unsupervised hierarchical clustering analysis revealed distinct microRNA sets in OA-EVs as compared to their parental MSCs or H-EVs. Pathway analysis of OA-EV miRNAs showed the enrichment of miRNAs implicated in chondrogenesis, stem cells, or other pathways related to cartilage and OA. In conclusion, OA SB MSCs were capable of producing EVs that could support chondrocyte viability and chondrogenic gene expression and contained microRNAs implicated in chondrogenesis support. These EVs could therefore mediate the cross-talk between the SB and cartilage in OA potentially modulating chondrocyte viability and endogenous cartilage regeneration.

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“…Although members of the let-7 family were not among the 7 miRNA signature determined in the current study, we did observe a strong correlation for levels of multiple family members (ρ > |0.6| for let-7a-5p, let-7d-5p, let-7e-5p, let-7f-5p, and let-7g-5p) to the expression of early markers, specifically to EGFLAM . More recently, Ali et al performed miRNA sequencing to identify a 7-miRNA-signature of early knee OA patients (miR-191-3p, miR-199a-5p, miR-335-3p, miR-335-5p, miR-543, miR-671-3p, and miR-1260b) [ 16 ]. Possibly, as a result of the different approach we took, aiming to identify a panel that could serve for both hip and knee OA, there was no overlap with the miRNAs identified in the current study.…”

Section: Discussionmentioning

confidence: 99%

“…The first ncRNA with potential predictive value for severe knee or hip OA was let-7e, identified in 2014 by microarray screening [ 14 ]. In the years following identification of the first predictive OA miRNA, more analyses have been performed that added circulating miRNAs with potential value as biomarkers, such as miR-140-3p, miR-33b-3p, and miR-671-3p, marking the radiographic severity of OA [ 15 , 16 ]. While clinical and radiological examination is commonly used for diagnosis of OA, early OA pathophysiology is reflected by changes in gene expression in human articular cartilage even before it becomes apparent on radiographs.…”

Section: Introductionmentioning

confidence: 99%

Circulating MicroRNAs Highly Correlate to Expression of Cartilage Genes Potentially Reflecting OA Susceptibility—Towards Identification of Applicable Early OA Biomarkers

et al. 2021

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Objective: To identify and validate circulating micro RNAs (miRNAs) that mark gene expression changes in articular cartilage early in osteoarthritis (OA) pathophysiology process. Methods: Within the ongoing RAAK study, human preserved OA cartilage and plasma (N = 22 paired samples) was collected for RNA sequencing (respectively mRNA and miRNA). Spearman correlation was determined for 114 cartilage genes consistently and significantly differentially expressed early in osteoarthritis and 384 plasma miRNAs. Subsequently, the minimal number of circulating miRNAs serving to discriminate between progressors and non-progressors was assessed by regression analysis and area under receiver operating curves (AUC) was calculated with progression data and plasma miRNA sequencing from the GARP study (N = 71). Results: We identified strong correlations (ρ ≥ |0.7|) among expression levels of 34 unique plasma miRNAs and 21 genes, including 4 genes that correlated with multiple miRNAs. The strongest correlation was between let-7d-5p and EGFLAM (ρ = −0.75, P = 6.9 × 10−5). Regression analysis of the 34 miRNAs resulted in a set of 7 miRNAs that, when applied to the GARP study, demonstrated clinically relevant predictive value with AUC > 0.8 for OA progression over 2 years and near-clinical value for progression over 5 years- (AUC = 0.8). Conclusions: We show that plasma miRNAs levels reflect gene expression levels in cartilage and can be exploited to represent ongoing pathophysiological processes in articular cartilage. We advocate that identified signature of 7 plasma miRNAs can contribute to direct further studies toward early biomarkers predictive for progression of osteoarthritis over 2 and 5 years.

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Sequencing identifies a distinct signature of circulating microRNAs in early radiographic knee osteoarthritis

Cited by 48 publications

References 45 publications

Mouse microRNA signatures in joint ageing and post-traumatic osteoarthritis

Mouse microRNA signatures in joint ageing and post-traumatic osteoarthritis

Characterization and miRNA Profiling of Extracellular Vesicles from Human Osteoarthritic Subchondral Bone Multipotential Stromal Cells (MSCs)

Circulating MicroRNAs Highly Correlate to Expression of Cartilage Genes Potentially Reflecting OA Susceptibility—Towards Identification of Applicable Early OA Biomarkers

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