MicroRNA‐34a‐5p Promotes Joint Destruction During Osteoarthritis

Abstract

Objective. MicroRNA-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. Methods. Expression 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). Wildtype (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. Results. Expression 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. Conclusion. Our findings provide comprehensive evidence of the role and therapeutic potential of miR-34a-5p in OA.

Oligonucleotide Therapies in the Treatment of Inflammatory Joint Disease

“…Similarly, intra-articular injection of antagomir-21-5p significantly attenuated the severity of OA in the DMM model, via modulating expression of FGF18 [88]. Furthermore, intra-articular injection of antisense oligonucleotides targeting miR-34a-5p was chondroprotective in a murine DMM model and in a high-fat diet/DMM model [89], whilst LNA antisense inhibition of miR-449a via intra-articular injection (100 nM injections twice weekly for 8 weeks) promoted cartilage regeneration, expression of type II collagen and aggrecan in a rat acute cartilage defect model after 4 and 8 weeks post-surgery and in a rat DMM model [90].…”

Systemic versus local adipokine expression differs in a combined obesity and osteoarthritis mouse model

“…Systemic adipokine level seem to be mainly responsible for energy homeostasis as mice lacking the leptin receptor display massive obesity 44 and on the other hand adiponectin knockout mice seem to be more susceptible to diet-induced insulin resistance 45 . However, miR-34a-5p was recently shown to be upregulated in plasma and knee joints of DMM mice fed with HFD 46 . This and other studies suggest that epigenetic changes may contribute to lasting pro-osteoarthritic effects induced by HFD.…”

Mesenchymal Stem Cell-Derived Exosomes and MicroRNAs in Cartilage Regeneration: Biogenesis, Efficacy, miRNA Enrichment and Delivery

“…Interestingly, the overexpression of hsa-miR-25-3p [180], hsa-miR-106a-5p [181], hsa-miR-126-3p [182], and hsa-miR-665 [183] has recently been reported to inhibit chondrocyte apoptosis and/or suppress chondrocyte inflammation and cartilage degradation. Another study uncovered the role of hsa-miR-34a-5p, which promotes joint destruction during OA [184]. Based on the above information and direct interpretation, it seems priming could enrich cartilage-protecting miRNAs and downregulate cartilage-degrading miRNAs in exosomes.…”