Abstract
Osteoarthritis (OA) is a degenerative disease characterized by synovial inflammation. MiR-18a-3p was reported to be downregulated in knee anterior cruciate ligament of OA patients. In the present study, the specific functions and mechanism of miR-18a-3p in OA were explored. An in vitro model of OA was established using 10 ng/ml IL-1β to treat ATDC5 cells, and medial meniscus instability surgery was performed on Wistar rats to establish in vivo rat model of OA. RT-qPCR revealed that miR-18a-3p was downregulated in IL-1β-stimulated ATDC5 cells. MiR-18a-3p overexpression inhibited secretion of inflammatory cytokines and concentration of matrix metalloproteinases, as shown by ELISA and western blotting. The binding relation between miR-18a-3p and pyruvate dehydrogenase phosphatase catalytic subunit 1 (PDP1) was detected by luciferase reporter assays. MiR-18a-3p targeted PDP1 and negatively regulated PDP1 expression. Results of rescue assays revealed that PDP1 upregulation reserved the suppressive effect of miR-18a-3p overexpression on levels of inflammatory cytokines and matrix metalloproteinases in IL-1β-stimulated ATDC5 cells. H&E staining was used to observe pathological changes of synovial tissues in the knee joint of Wistar rats. Safranin O-fast green/hematoxylin was used to stain cartilage samples of knee joints. MiR-18a-3p overexpression suppressed OA progression in vivo. Overall, miR-18a-3p improves cartilage matrix remodeling and suppresses inflammation in OA by targeting PDP1.
Highlights
Osteoarthritis (OA) is an articular joint disease with high morbidity in the elderly people [1]
After interleukin 1β (IL-1β) treatment, we observed that miR-18a-3p expression in ATDC5 cells was downregulated (Fig. 1A). miR-18a-3p expression was increased in ATDC5 cells after transfection with miR18a-3p mimic (Fig. 1B)
The results showed that IL-1β increased the release of these inflammatory cytokines in ATDC5 cells, and miR-18a-3p overexpression reversed IL-1β-induced increase in cytokines (Fig. 1C–E)
Summary
Osteoarthritis (OA) is an articular joint disease with high morbidity in the elderly people [1]. The etiological factors of OA include obesity, heredity, cardiovascular diseases, aging, genetic factors and joint injury [3]. The main pathological changes of OA are articular cartilage degeneration, inflammation of synovitis, and secondary bone hyperplasia [7, 8]. A connective tissue with high specialization, is composed of chondrocytes and extracellular matrix [9]. Chondrocytes synthesize extracellular matrix to maintain the structural and functional integrity of the cartilage [10]. Chondrocytes are difficult to maintain cartilage homeostasis in response to OA stimulation [11]. Chondrocyte catabolism can be stimulated by inflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and prostaglandin E2 (PGE2) [10]. Many previous studies verified that inflammation in the synovitis is a key factor leading to OA progression [10, 13, 14]
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