Abstract
Osteoarthritis (OA), characterized by insufficient extracellular matrix synthesis and cartilage degeneration, is known as an incurable disease because its pathogenesis is poorly elucidated. Thus far, limited information is available regarding the pathophysiological role of microRNAs (miRNAs) in OA. In this study, we investigated the specific function of miR-146a in OA pathophysiology using mouse OA models. We found that the articular cartilage degeneration of miR-146a knockout (KO) mice was alleviated compared with that of the wild-type (WT) mice in spontaneous and instability-induced OA models. We demonstrate that miR-146a aggravated pro-inflammatory cytokines induced suppressing the expression of cartilage matrix-associated genes. We further identified calcium/calmodulin-dependent protein kinase II delta (Camk2d) and protein phosphatase 3, regulatory subunit B, beta isoform (Ppp3r2, also known as calcineurin B, type II) were essential targets of miR-146a in regulating cartilage homeostasis. Moreover, we found that surgical-induced OA mice treated with a miR-146a inhibitor significantly alleviated the destruction of articular cartilage via targeting Camk2d and Ppp3r2. These results suggested that miR-146a has a crucial role in maintaining cartilage homeostasis. MiR-146a inhibition in chondrocytes can be a potential therapeutic strategy to ameliorate OA.
Highlights
Osteoarthritis (OA) is the most prevalent musculoskeletal disease in the elderly, and it is predicted to affect 60 million people in the United States by 2020.1,2 effective disease-modifying therapies for OA are unavailable because of the limited understanding of the disease pathogenesis; as such, joint replacement remains the preferred treatment for patients with advanced OA.[3]
We found that IL-1β, IL-17 and TNF-α upregulated the expression of miR-146a in mouse primary chondrocytes, whereas the other inflammatory cytokines had no effect on miR-146a expression (Figure 3d)
For the miRNAs downregulated by pro-inflammatory cytokines, previous reports suggest that induction of MMPs and catabolic enzymes by IL-1β were regulated by suppression of miR-140, for example, miR-140 targets Adamts[5], which mediate degeneration of articular cartilage.[14]
Summary
Osteoarthritis (OA) is the most prevalent musculoskeletal disease in the elderly, and it is predicted to affect 60 million people in the United States by 2020.1,2 effective disease-modifying therapies for OA are unavailable because of the limited understanding of the disease pathogenesis; as such, joint replacement remains the preferred treatment for patients with advanced OA.[3]. OA is primarily characterized by degradation of the articular cartilage, as well as subchondral bone sclerosis, and osteophyte formation.[4,5] It is suggested that OA is caused by the disruption of cartilage homeostatic balance between anabolic and catabolic signals.[6,7] Various risk factors, such as abnormal mechanics, aging and inflammation, have been identified to contribute to cartilage destruction.[8,9,10] A better understanding of the underlying molecular mechanisms of deranged cartilage homeostasis may help to develop new treatments for OA. MiR-146a is intensely expressed in cartilage in early OA, and it is strongly upregulated by IL-1β stimulation in cultured normal human articular cartilage chondrocytes.[16] It has been suggested that miR-146a functions as a negative feedback regulator of pro-inflammatory signaling pathways by targeting TNF receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1) in the THP-1 human monocytic cell line.[17] the exact role of miR-146a in the pathogenesis of OA remains unknown. Tel: +862 163 139920 or +862 154 923338; Fax: +862 163 139920 or +862 154 923338; Received 27.10.16; revised 25.1.17; accepted 01.3.17; Edited by G Calin miR-146a facilitates osteoarthritis development X Zhang et al
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