OP0018 MIR-34A IS A POTENTIAL THERAPEUTIC TARGET IN OSTEOARTHRITIS. (June 2019)

• Record Type: Journal Article
• Authors: Endisha, Helal; Datta, Poulami; Sharma, Anirudh; Nakamura, Sayaka; Rossomacha, Evgeny; Younan, Carolen; Tavallaee, Ghazaleh; Gandhi, Rajiv; Kapoor, Mohit
• Is Part Of: Annals of the rheumatic diseases. Volume 78(2019)Supplement 2
• Page Start: 75
• Page End: 76
• Publication Date: 2019-06
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2019-eular.2677
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: We have previously reported that microRNA-34a (miR-34a) is expressed at significantly higher levels in the synovial fluid of late-stage radiographic knee osteoarthritis (OA) compared to early-stage radiographic knee OA. Despite increased levels of miR-34a, its exact role in OA pathogenesis is largely unknown. The aim of this study was to comprehensively elucidate the role and therapeutic potential of microRNA-34 in OA. Objectives: The aim of this study was to comprehensively elucidate the role and therapeutic potential of microRNA-34 in OA. Methods: Human plasma, cartilage and synovium were obtained from total knee replacement (TKR) patients. Chondrocytes and synovial fibroblasts were transfected with miR-34a mimic or inhibitor for qRT-PCR or Western blot. For in-vivo studies, mice were injected once with a in-vivo grade mir-34a mimic or control oligonucleotide and joints were collected 8 weeks post-injection for histology. Mice were subjected to destabilization of the medial meniscus (DMM) to induce OA and injected 2, 4, and 6 weeks post-surgery with miR-34a inhibitor and joints were collected 10 weeks post-surgery for histology. Heterozygous miR-34a knock out (KO) mice were bred to generate homozygous KOs and mouse articular cartilage was isolated to culture chondrocytes. Results: miR-34a expression was significantly elevated in the plasma as well as cartilage and synovium of TKR patients (KL IV) compared to healthy controls and early OA patients (KL-I), respectively. Similarly, miR-34a was significantly overexpressed in mouse knee joints (cartilage and synovium) at 10 weeks post OA surgery compared to sham. To identify the biological effects of miR-34a on chondrocyte and synovial fibroblast (SF), functional studies were conducted in-vitro . Chondrocytes treated with miR-34a mimic had a significant reduction of SIRT1 (a direct target of miR-34a), anabolic (type II collagen and aggrecan) and autophagy markers, as well as, elevated catabolic markers (MMP13), suggesting that miR-34a contributes to cartilage degeneration. Chondrocytes treated with mir-34a inhibitor reversed these destructive effects. SFs treated with miR-34a mimic expressed elevated inflammatory (TNF-α, IL-6), fibrotic (TGF-β, Type 1 Collagen), and autophagy markers, suggesting that miR-34a is involved in mediating synovial inflammation and fibrosis. SFs treated with miR-34a inhibitor reversed these effects. In vivo, intra-articular injection of miR-34a mimic induced cartilage damage, loss of proteoglycan content, and elevated cell death markers (PARP p85 and Caspase 3) in the articular cartilage. To confirm the destructive effects of miR-34a in the articular cartilage, we used miR-34a KO mice. MiR-34a KO mice further confirmed that genetic ablation of miR-34a resulted in marked elevation in the expression of anabolic markers (type II collagen and aggrecan) and decreased expression of catabolic ADAMTS-5 in the articular cartilage. To test the therapeutic potential of blocking miR-34a, we intra-articularly injected mir-34a inhibitor in mice subjected to OA surgery. Results showed marked reduction in the severity of cartilage degeneration in mice treated with miR-34a inhibitor. Conclusion: This study, for the first time, demonstrates miR-34a as a crucial mediator involved in OA pathogenesis and as a potential therapeutic target for limiting cartilage destruction during OA. Disclosure of Interests: None declared