Dataset Information

MicroRNA-218-5p as a Potential Target for the Treatment of Human Osteoarthritis.

ABSTRACT: Emerging evidence suggests that dysregulated microRNAs (miRNAs) play a pivotal role in osteoarthritis (OA), but the role of specific miRNAs remains unclear. Accordingly, we identified OA-associated miRNAs and functional validation of results. Here, we demonstrate that miR-218-5p is significantly upregulated in moderate and severe OA and correlates with scores on a modified Mankin scale. Through gain-of-function and loss-of-function studies, miR-218-5p was shown to significantly affect matrix synthesis gene expression and chondrocyte proliferation and apoptosis. Using SW1353 and C28/I2 cells, PIK3C2A mRNA was identified as a target of miR-218-5p. Downregulation of miR-218-5p dramatically promoted expression of PIK3C2A and its downstream target proteins, such as Akt, mTOR, S6, and 4EBP1. More importantly, OA mice exposed to a miR-218-5p inhibitor were protected from cartilage degradation and had reduced proteoglycan loss and reduced loss of articular chondrocyte cellularity compared with control mice. miR-218-5p is a novel inducer of cartilage destruction via modulation of PI3K/Akt/mTOR signaling. Inhibition of endogenous miR-218-5p expression/activity appears to be an attractive approach to OA treatment.

SUBMITTER: Lu J

PROVIDER: S-EPMC5768591 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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MicroRNA-218-5p as a Potential Target for the Treatment of Human Osteoarthritis.

Lu Jun J Ji Ming-Liang ML Zhang Xue-Jun XJ Shi Pei-Liang PL Wu Hao H Wang Chen C Im Hee-Jeong HJ

Molecular therapy : the journal of the American Society of Gene Therapy 20170819 12

Emerging evidence suggests that dysregulated microRNAs (miRNAs) play a pivotal role in osteoarthritis (OA), but the role of specific miRNAs remains unclear. Accordingly, we identified OA-associated miRNAs and functional validation of results. Here, we demonstrate that miR-218-5p is significantly upregulated in moderate and severe OA and correlates with scores on a modified Mankin scale. Through gain-of-function and loss-of-function studies, miR-218-5p was shown to significantly affect matrix syn ...[more]

PMID: 28919376

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Project description:ObjectiveMicroRNA-34a-5p (miR-34a-5p) expression is elevated in the synovial fluid of patients with late-stage knee osteoarthritis (OA); however, its exact role and therapeutic potential in OA remain to be fully elucidated. This study was undertaken to examine the role of miR-34a-5p in OA pathogenesis.MethodsExpression of miR-34a-5p was determined in joint tissues and human plasma (n = 71). Experiments using miR-34a-5p mimic or antisense oligonucleotide (ASO) treatment were performed in human OA chondrocytes, fibroblast-like synoviocytes (FLS) (n = 7-9), and mouse OA models, including destabilization of the medial meniscus (DMM; n = 22) and the accelerated, more severe model of mice fed a high-fat diet and subjected to DMM (n = 11). Wild-type (WT) mice (n = 9) and miR-34a-knockout (KO) mice (n = 11) were subjected to DMM. Results were expressed as the mean ± SEM and analyzed by t-test or analysis of variance, with appropriate post hoc tests. P values less than 0.05 were considered significant. RNA sequencing was performed on WT and KO mouse chondrocytes.ResultsExpression of miR-34a-5p was significantly increased in the plasma, cartilage, and synovium of patients with late-stage OA and in the cartilage and synovium of mice subjected to DMM. Plasma miR-34a-5p expression was significantly increased in obese patients with late-stage OA, and in the plasma and knee joints of mice fed a high-fat diet. In human OA chondrocytes and FLS, miR-34a-5p mimic increased key OA pathology markers, while miR-34a-5p ASO improved cellular gene expression. Intraarticular miR-34a-5p mimic injection induced an OA-like phenotype. Conversely, miR-34a-5p ASO injection imparted cartilage-protective effects in the DMM and high-fat diet/DMM models. The miR-34a-KO mice exhibited protection against DMM-induced cartilage damage. RNA sequencing of WT and KO chondrocytes revealed a putative miR-34a-5p signaling network.ConclusionOur findings provide comprehensive evidence of the role and therapeutic potential of miR-34a-5p in OA.

Project description:Early detection of acute kidney injury is difficult due to lack of known biomarkers; previous studies have tried to identify new biomarkers for detecting acute kidney injury at an early stage. MicroRNA, a 21-23 nucleotide noncoding RNA molecule, has emerged as a desirable marker in the diagnosis and prognosis of various diseases. This study aims to identify the expression profile of microRNA in ischemia-reperfusion-induced kidney injury and determine the possibility of using the candidate microRNA as biomarker for the detection of I/R-induced kidney injury. Based on the established rat model of I/R-induced kidney injury, a microarray analysis of rat urine was performed at the beginning of operation (0 h) as well as 72 h post operation. To validate the results, urine samples from 71 patients who underwent cardiac surgery were collected, after which urinalysis was conducted to determine the microRNA concentration. An alternative expression profile of microRNAs was detected in rat urine. The quantitative validation of microRNA showed that the expression of miR-30c-5p, miR-192-5p, and miR-378a-3p was elevated significantly in urine post operation, which was consistent with those of the microarray analysis and earlier than kidney injury molecule-1 (KIM-1). In patients with acute kidney injury, increased levels of miR-30c-5p and miR-192-5p were also detected 2 h post operation, and miR-30c-5p showed preferable diagnostic value compared with protein-based biomarkers. In conclusion, an aberrant expression profile of microRNA was detected in rat urine based on the established ischemia-reperfusion animal model. Both miR-30c-5p and miR-192-5p served as important potential diagnostic markers for I/R-induced kidney injury. Impact statement Firstly, one differentiating factor in our study is that the candidate miRNAs were screened in a controlled animal model rather than in patients with acute kidney injury (AKI) to ensure the purity of the cause of disease and to avoid possible effects of comorbidities on the spectrum of urine miRNA. This ensured the presence of only the relevant candidate miRNA (that associated with I/R injury); and what's more, the alterative expression of miR-192-5p and miR-30c-5p in animal model, patients with AKI, and cell model was confirmed simultaneously, which is likely to be more convincing. Secondly, the candidate miRNAs were screened sequentially at regular time points, which covered the initiation, progression, and partial repair stages, thus ensuring that no significant miRNAs were omitted in the screening process, and miR-biomarkers in 2 h post operation showed preferable diagnostic performance.

Dataset Information

MicroRNA-218-5p as a Potential Target for the Treatment of Human Osteoarthritis.

Publications

MicroRNA-218-5p as a Potential Target for the Treatment of Human Osteoarthritis.

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