Expression of miR-34a-5p was significantly increased in the plasma, cartilage, and synovium of patients with late-stage osteoarthritis.
Increased levels of miR-34a-5p were also observed in the cartilage and synovium of mice subjected to destabilization of the medial meniscus.
Obese patients with late-stage osteoarthritis had significantly higher plasma levels of miR-34a-5p compared to non-obese patients.
In human osteoarthritis chondrocytes and fibroblast-like synoviocytes, miR-34a-5p mimic treatment elevated key markers associated with osteoarthritis pathology.
Injection of miR-34a-5p mimic into joints induced an osteoarthritis-like phenotype in mouse models.
Conversely, injection of miR-34a-5p antisense oligonucleotide improved gene expression and exhibited cartilage-protective effects in mouse models.
Mice lacking miR-34a demonstrated protection against cartilage damage induced by destabilization of the medial meniscus.
Simplified
OBJECTIVE: (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). 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.
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.
Key numbers
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Increased miR-34a-5p in OA patients
Patients with late-stage knee OA showed elevated miR-34a-5p levels.
22 vs. 29
Obese vs. nonobese OA patients
Obese OA patients had significantly higher miR-34a-5p levels than nonobese patients.
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