MicroRNA-34a-5p Promotes Joint Destruction during Osteoarthritis.

OBJECTIVES MicroRNA-34a-5p (miR-34a-5p) expression is elevated in the synovial fluid of late-stage knee osteoarthritis (OA); however, its exact role and therapeutic potential in OA remains to be fully elucidated. METHODS MiR-34a-5p expression was determined in joint tissues and human plasma (n=71). miR-34a-5p mimic or antisense-oligonucleotide (ASO) treatment experiments 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 high-fat diet (HFD)-fed mice subjected to DMM (n=11). Wild-type (WT) (n=9) and miR-34a-knock-out (KO) mice (n=11) were subjected to DMM. Results were expressed as mean±standard error of mean and analyzed by t-test or ANOVA, with appropriate post-hoc tests. P<0.05 was considered statistically significant. RNA-sequencing was performed on WT and KO mouse chondrocytes. RESULTS MiR-34a-5p expression was significantly increased in plasma, cartilage and synovium of late-stage OA patients and in cartilage and synovium of mice subjected to DMM. Plasma miR-34a-5p expression was significantly increased in obese late-stage OA patients, and in plasma and knee joints of HFD-fed mice. In human OA chondrocytes and FLS, miR-34a-5p mimic increased key OA pathology markers, while miR-34a-5p ASO improved cellular gene expression. Intra-articular miR-34a-5p mimic injection induced an OA-like phenotype. Conversely, miR-34a-5p ASO injection imparted cartilage-protective effects in DMM and HFD-DMM models. MiR-34a-KOs exhibited protection from DMM-induced cartilage damage. RNA-sequencing of WT and KO chondrocytes revealed a putative miR-34a-5p signaling network. CONCLUSIONS This study provides comprehensive evidence on the role and therapeutic potential of miR-34a-5p in OA.