MicroRNA-34a-5p Promotes Joint Destruction During Obesity and Osteoarthritis

Osteoarthritis (OA) is a chronic degenerative joint disease and the most common cause of disability among older individuals. We previously found that levels of microRNA-34a-5p (miR-34a-5p) in synovial fluid increase during late-stage (grade III/IV) compared to grade I/II radiographic knee OA; however, the role of miR-34a-5p in OA pathophysiology and its potential as a therapeutic target is largely unknown. In the current study, I found that miR-34a-5p expression was increased in the plasma, knee articular cartilage and synovial tissue of total knee replacement (TKR) patients compared to healthy controls and early OA synovial tissue. Similarly, miR-34a-5p expression was increased in knee joint tissues of a surgically-induced (destabilization of medial meniscus (DMM)) mouse model of OA. Since obesity is a significant risk factor for OA development, I first showed that plasma miR-34a-5p expression was further elevated in obese versus non obese OA patients. In addition, miR-34a-5p expression was highly elevated in plasma and knee joints of obese mice subjected to high fat diet. My in vitro studies revealed that miR-34a-5p mimic promoted critical mediators involved in catabolic processes in human chondrocytes and increased expression of synovitis-associated markers in human fibroblast-like synoviocytes (FLS). Conversely, miR-34a-5p antisense oligonucleotide (ASO) treatment promoted anabolic effects in chondrocytes and reduced the expression of pro-fibrotic and pro-inflammatory markers in FLS. In conjunction with my in vitro findings, intra-articular injection of miR-34a-5p mimic in mice induced OA pathological changes such as cartilage degeneration and synovitis. Notably, my preclinical studies conclusively demonstrated the therapeutic potential of intra-articular injections of miR-34a-5p ASO, which imparted cartilage-protective effects in both normal weight and high-fat diet-fed mice subjected to OA surgery. To investigate the regulatory mechanisms of miR-34a-5p in articular cartilage, chondrocytes obtained from miR-34a knock out (KO) mice or wild-types (WT) were subjected to RNA Sequencing and putative signaling pathways regulated by miR-34a-5p were determined. This is the first study to propose a link between obesity and OA via dysregulated miR-34a-5p expression and provides first preclinical evidence for OA therapeutic intervention using a miR-34a-5p ASO.Ph.D.2020-11-13 00:00:0