The Emerging Role of Non-Coding RNAs in Osteoarthritis

Abstract

Osteoarthritis (OS) is the most frequent degenerative condition in the joints, disabling many adults. Several abnormalities in the articular cartilage, subchondral bone, synovial tissue, and meniscus have been detected in the course of OA. Destruction of articular cartilage, the formation of osteophytes, subchondral sclerosis, and hyperplasia of synovial tissue are hallmarks of OA. More recently, several investigations have underscored the regulatory roles of non-coding RNAs (ncRNAs) in OA development. Different classes of non-coding RNAs, including long ncRNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), have been reported to affect the development of OA. The expression level of these transcripts has also been used as diagnostic tools in OA. In the present article, we aimed at reporting the role of these transcripts in this process. We need to give a specific angle on the pathology to provide meaningful thoughts on it.

Keywords: circRNA; expression; lncRNA; miRNA; ncRNAs; osteoarthritis.

Figure 1

A schematic illustration of the role of various noncoding-RNAs in modulating the JAK/STAT and NF-κB signaling pathways in osteoarthritis. Mounting studies have revealed that multiple ncRNAs (lncRNAs, circRNAs, and miRNAs) have important roles in osteoarthritis through regulating the JAK/STAT and NF-κB cascades. As an illustration, lncRNA PVT1 could play an effective role in upregulating TLR4/NF-κB signaling cascade via modulating miR-93-5p/HMGB1 axis in osteoarthritis patients, therefore inducing osteoarthritis development (28). In addition, lncRNA-ATB overexpression could have a crucial part in downregulating the expression levels of iNOS, COX-2, IL-6 and TNF-α proteins. These lncRNA could reduce miR-223 expression through suppressing MyD88/NF-κB and p38MAPK cascades, and thereby alleviating lipopolysaccharide-induced inflammatory injury in osteoarthritis patients (56). Another study has confirmed that lncRNA SNHG1 through downregulating the expression levels of IL-6, TNF-α, iNOS, COX-2, ERK1/2, P38, and P65 as well as suppressing miR-16-5p-mediated p38MAPK and NF-κB signaling cascades could have an effective role in alleviating IL-1β-induced osteoarthritis (51). Green arrows indicate the upregulation of target genes modulated via ncRNAs (lncRNAs, circRNAs, and miRNAs), red arrows depict inhibition regulated by these ncRNAs. All the information regarding the role of up-regulated or down-regulated ncRNAs in modulating osteoarthritis can be seen in Tables 1 – 7 .

Figure 2

A schematic representation of the role of several ncRNAs in regulating the autophagy cascade in osteoarthritis. Growing evidence confirm that several ncRNAs could regulate the autophagy pathway in osteoarthritis. A recent study have authenticated that lncRNA HOTAIR through downregulating the expression levels of miR‐130a‐3p, P62, LC3 I, LC3 II could play a significant role in suppressing chondrocyte autophagy in knee osteoarthritis (10). Moreover, according to another research, ciRS-7 through sponging miR-7 and reducing the expression levels of LC3, p62, and Beclin1 could reduce cartilage degradation and attenuate autophagy cascade in osteoarthritis via modulating PI3K/AKT/mTOR pathway (92). Red arrows indicate downregulation of target genes by ncRNAs.

Figure 3

A schematic diagram of the role of some ncRNAs in modulating the PI3K/AKT and Wnt/β-catenin signaling pathways in osteoarthritis. Current research has demonstrated that circRNA-9119 via sponging miR-26a could have a significant part in promoting the expression level of PTEN. These circRNA could suppress IL-1β-induced chondrocyte apoptosis, and possibly triggering Osteoarthritis progression (93). Moreover, another study has denoted that lncRNA HOTAIR could enhance the activation of Wnt/β-catenin signaling cascade via downregulating WIF-1 expression in osteoarthritic chondrocytes by promoting the expression levels of c-Myc, ZEB1, and Snail as downstream target genes of Wnt/β-catenin signaling, thereby elevating catabolic gene expression and increasing cartilage degradation (7). Green arrows indicate upregulation of target genes via ncRNAs (lncRNAs, circRNAs, and miRNAs), red arrows depict inhibition by these ncRNAs. All the information regarding the role of these ncRNAs in modulating the PI3K/AKT and Wnt/β-catenin cascades in osteoarthritis can be seen in Tables 1 – 7 .