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      Regulatory mechanism of circular RNA involvement in osteoarthritis

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          Abstract

          Osteoarthritis (OA) causes joint pain, stiffness, and dysfunction in middle-aged and older adults; however, its pathogenesis remains unclear. Circular RNAs (circRNAs) are differentially expressed in patients with OA and participate in a multigene, multitarget regulatory network. CircRNAs are involved in the development of OA through inflammatory responses, including proliferation, apoptosis, autophagy, differentiation, oxidative stress, and mechanical stress. Most circRNAs are used as intracellular miRNA sponges in chondrocytes, endplate chondrocytes, mesenchymal stem cells, synoviocytes, and macrophages to promote the progression of OA. However, a small portion of circRNAs participates in the pathogenesis of OA by intracellular mechanisms, such as protein binding, methylation, or intercellular exosome pathways. In this sense, circRNAs might serve as potential novel biomarkers and therapeutic targets for OA.

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          Most cited references82

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          Circular RNAs are a large class of animal RNAs with regulatory potency.

          Circular RNAs (circRNAs) in animals are an enigmatic class of RNA with unknown function. To explore circRNAs systematically, we sequenced and computationally analysed human, mouse and nematode RNA. We detected thousands of well-expressed, stable circRNAs, often showing tissue/developmental-stage-specific expression. Sequence analysis indicated important regulatory functions for circRNAs. We found that a human circRNA, antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as), is densely bound by microRNA (miRNA) effector complexes and harbours 63 conserved binding sites for the ancient miRNA miR-7. Further analyses indicated that CDR1as functions to bind miR-7 in neuronal tissues. Human CDR1as expression in zebrafish impaired midbrain development, similar to knocking down miR-7, suggesting that CDR1as is a miRNA antagonist with a miRNA-binding capacity ten times higher than any other known transcript. Together, our data provide evidence that circRNAs form a large class of post-transcriptional regulators. Numerous circRNAs form by head-to-tail splicing of exons, suggesting previously unrecognized regulatory potential of coding sequences.
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            Natural RNA circles function as efficient microRNA sponges.

            MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that act by direct base pairing to target sites within untranslated regions of messenger RNAs. Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants. We previously identified a highly expressed circular RNA (circRNA) in human and mouse brain. Here we show that this circRNA acts as a miR-7 sponge; we term this circular transcript ciRS-7 (circular RNA sponge for miR-7). ciRS-7 contains more than 70 selectively conserved miRNA target sites, and it is highly and widely associated with Argonaute (AGO) proteins in a miR-7-dependent manner. Although the circRNA is completely resistant to miRNA-mediated target destabilization, it strongly suppresses miR-7 activity, resulting in increased levels of miR-7 targets. In the mouse brain, we observe overlapping co-expression of ciRS-7 and miR-7, particularly in neocortical and hippocampal neurons, suggesting a high degree of endogenous interaction. We further show that the testis-specific circRNA, sex-determining region Y (Sry), serves as a miR-138 sponge, suggesting that miRNA sponge effects achieved by circRNA formation are a general phenomenon. This study serves as the first, to our knowledge, functional analysis of a naturally expressed circRNA.
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              circRNA biogenesis competes with pre-mRNA splicing.

              Circular RNAs (circRNAs) are widely expressed noncoding RNAs. However, their biogenesis and possible functions are poorly understood. Here, by studying circRNAs that we identified in neuronal tissues, we provide evidence that animal circRNAs are generated cotranscriptionally and that their production rate is mainly determined by intronic sequences. We demonstrate that circularization and splicing compete against each other. These mechanisms are tissue specific and conserved in animals. Interestingly, we observed that the second exon of the splicing factor muscleblind (MBL/MBNL1) is circularized in flies and humans. This circRNA (circMbl) and its flanking introns contain conserved muscleblind binding sites, which are strongly and specifically bound by MBL. Modulation of MBL levels strongly affects circMbl biosynthesis, and this effect is dependent on the MBL binding sites. Together, our data suggest that circRNAs can function in gene regulation by competing with linear splicing. Furthermore, we identified muscleblind as a factor involved in circRNA biogenesis. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Front Surg
                Front Surg
                Front. Surg.
                Frontiers in Surgery
                Frontiers Media S.A.
                2296-875X
                06 January 2023
                2022
                : 9
                : 1049513
                Affiliations
                [ 1 ]Inner Mongolia Medical University , Hohhot, China
                [ 2 ]Department of Clinical Laboratory, The Affiliated Hospital of Inner Mongolia Medical University , Hohhot, China
                [ 3 ]Clinical Medicine Research Center, The Affiliated Hospital of Inner Mongolia Medical University , Hohhot, China
                [ 4 ]Department of Orthopedics and Traumatology, The Second Affiliated Hospital of Inner Mongolia Medical University , Hohhot, China
                Author notes

                Edited by: Qiling Yuan, Xi'an Jiaotong University, China

                Reviewed by: Yu Kuan Tang, Guangzhou Panyu Central Hospital, China Binglin Yue, Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, China

                [* ] Correspondence: Xiulan Su xlsu2014@ 123456163.com ; Jianzhong Wang wangjianzhongwj@ 123456163.com
                [ † ]

                These authors have contributed equally to this work and share first authorship

                Specialty Section: This article was submitted to Orthopedic Surgery, a section of the journal Frontiers in Surgery

                Article
                10.3389/fsurg.2022.1049513
                9852714
                36684373
                d731ebd8-c818-453f-a009-c8eb8f52d2fb
                © 2023 Zhang, Liu, Liu, Wang, Su and Wang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 20 September 2022
                : 23 November 2022
                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 83, Pages: 0, Words: 0
                Funding
                Funded by: National Natural Science Foundation of China, doi 10.13039/501100001809;
                Award ID: 81860401
                Categories
                Surgery
                Review

                osteoarthritis,circular rna,cartilage degeneration,competitive endogenous rna,rna binding protein,exosomes,n6-methyladenosine

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