Abstract
Osteoarthritis (OA) is an aging-related chronic degenerative disease characterized by the degradation of chondrocyte extracellular matrix (ECM). Previous studies have suggested that microRNAs (miRNAs) are associated with OA, but the role of miR-146b in OA remains unclear. The aim of this study was to determine the role of miR-146b in OA progression. The effect of miR-146b on ECM degradation were studied in mouse chondrocytes transfected with miRNA and treated with IL-1β. Cell viability and the expression levels of proteolytic enzymes in the transfected cells were assessed by real-time RT-PCR, ELISA and Western blots. We found downregulation of miR-146b expression in chondrocytes dramatically inhibited IL-1β-induced caspase activation and proteolytic enzyme expression via influencing its targeted Alpha-2-macroglobulin (A2M). Luciferase reporter assays confirmed that A2M mRNA was negatively regulated by miR-146b in chondrocytes. Intra-articular injection of antago-miR-146b against miR-146b effectively protected mice from the progression of DMM-induced osteoarthritis by inhibiting cartilage proteoglycan degradation. Our study indicates that miR-146b plays a critical role in the progression of injury-induced osteoarthritis by directly targeting A2M expression to elevate the proteolytic enzyme production and stimulate chondrocytes apoptosis, and miR-146b as well as A2M could be therapeutic targets.
Highlights
Osteoarthritis (OA) is the most common degenerative disease caused by joint instability in the elderly [1, 2]
We found that IL-1β treatment of mouse chondrocytes increased miR-146b expression in a time-dependent manner, with highest expression of 4.28fold over the vehicle control 36 hours after treatment (Figure 1E)
We found that boosted level of miR-146b in chondrocytes remarkably decreased IL-1β-induced cell viability by 48% and increased IL-1β-stimulated cell apoptosis by 43%, while transfection of chondrocytes with miR-146b inhibitor increased cell viability by 39% and decreased apoptosis by 21% (Figure 2A, 2B)
Summary
Osteoarthritis (OA) is the most common degenerative disease caused by joint instability in the elderly [1, 2]. The main characteristic of OA includes progressive degeneration of articular cartilage, subchondral bone remodeling and joint inflammation that lead to severe joint pain and loss of function [3, 4]. Its pathogenesis of OA is not well understood and there is no curable medical therapy for this disease. Chondrocytes in cartilage function normally produce and secret the extracellular matrix proteins to maintain cartilage integrity [5]. The chondrocytes change their behavior, they become autophagy, overexpress the hypertrophy markers, and secrete disease-causal cytokines or small fragments of nucleic acid—such as microRNAs (miRNAs) to promote cell degeneration and apoptosis [6, 7]. MiRNAs, including miR-101 [10], miR-675 [11], miR-140 [12], miR-27a [13], miR-127-5P [14], miR-15a [15], and miR-
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