Abstract
Altered expression of circular RNAs (circRNAs) has been identified in various human diseases. In this study, we investigated whether circRNAs function as competing endogenous RNAs to regulate the pathological process of temporomandibular joint osteoarthritis (TMJOA). High-throughput sequencing of mRNA (RNA seq) was performed to detect the expression of circRNAs in TMJOA and control synovial tissues isolated from humans. The differentially upregulated circGCN1L1 (hsa_circ_0000448) in synoviocyte was validated in vitro and in vivo. Here we demonstrate the interactions between circGCN1L1 and both miR-330-3p and tumor necrosis factor-α (TNF-α) through bioinformatics predictions, luciferase report assays, and fluorescence in situ hybridization. mRNA expression profiles of TNF-α-stimulated synoviocyte showed that circGCN1L1 and p65 expressions were upregulated by TNF-α. Moreover, miR-330-3p was negatively correlated with TNF-α secretion. Further, we found that miR-330-3p directly targeted TNF and restrained the production of matrix-degrading enzymes (MMP3, MMP13, and ADAMTS4). Mechanistic studies unveiled that circGCN1L1 in TMJOA synovial tissues and cells may be associated with condylar chondrocyte apoptosis and synoviocyte hyperplasia. Moreover, intra-articular injection of shcircGCN1L1 alleviated TMJOA progression in rat models. Altogether, we elucidated the important roles of a novel circRNA, namely, circGCN1L1, which induced inflammation in TMJ synoviocytes and decreased anabolism of the extracellular matrix (ECM) through miR-330-3p and TNF-α gene. This circRNA may represent a potentially effective therapeutic strategy against TMJOA progression at an early stage.
Highlights
Temporomandibular joint (TMJ) osteoarthritis (OA) is one of the most common temporomandibular joint diseases and is characterized by joint clicking/noise, pain, and restricted mouth opening and mandible movements, which may affect sufferers physically or mentally and their daily activities[1]
Numerous studies have confirmed a high prevalence of synovial inflammation that persists through all stages of OA15–17
The pathological synovial tissues were acquired from patients with temporomandibular joint osteoarthritis (TMJOA) (Wilkes Stage 4) based on clinical symptoms and magnetic resonance imaging (MRI) diagnoses (N = 20: 5 for RNA seq, 10 for vitro RT-quantitative polymerase chain reaction (qPCR) validation, and 5 for vitro cell culture and other experiments)
Summary
Temporomandibular joint (TMJ) osteoarthritis (OA) is one of the most common temporomandibular joint diseases and is characterized by joint clicking/noise, pain, and restricted mouth opening and mandible movements, which may affect sufferers physically or mentally and their daily activities[1]. Researchers consider circRNAs key regulators of the inflammatory response induced by osteoarthritis and potential new therapeutic targets in OA6–9. Little is known about the functional roles of circRNAs in TMJOA, in the TMJOA synovium. Binding sites and to naturally sequester miRNAs and Official journal of the Cell Death Differentiation Association. Zhu et al Cell Death and Disease (2020)11:284 competitively inhibit miRNA activity[10]. Xiang et al.[12] detected 122 differentially expressed circRNAs in the OA synovium. Current research[13,14] on synovial inflammation is focused mainly on limb joints and has not examined the mechanism or function of circRNAs in synovial tissue. Researchers recognize that joint synovial lesions potentially play pivotal roles in the pathogenesis of osteoarthritis. We hypothesize that circRNAs may be central regulators of the TMJOA course
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