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      Circular RNAs: Promising Targets in Osteoporosis

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          Abstract

          Purpose of Review

          Circular RNAs (circRNAs) are RNA transcripts derived from fragments of pre-messenger RNAs through a back-splicing process. An advantage that rises from their circular covalently closed conformation is their high stability, when compared with their linear counterparts. The current review focuses on the emerging roles of circRNAs in osteoporosis, including in osteogenic differentiation and osteoclastogenesis. Their potential as osteoporosis biomarkers will also be discussed.

          Recent Findings

          Although firstly described as non-coding, some of these single-stranded RNAs were recently reported to possess protein-coding capacity. On the other hand, the circRNAs exhibit cell and tissue-specific patterns at the transcriptome level in eukaryotes and are regulated throughout the development or disease progression. Even though thousands of these circular transcripts are listed and annotated, only a limited number of studies describe their biological role in bone processes. Recent evidence indicates inhibitory activator roles in both osteoblasts and osteoclasts differentiation and function. Latest screenings in the blood, plasma, or serum of osteoporosis patients support the potential for circRNA signature to be used as biomarkers in osteoporosis, but further validation is required.

          Summary

          While intense research into circRNAs has been detailing their biological roles, there remains a need for standardization and further research to fulfil the future potential of this emerging and highly promising class of regulatory molecules.

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          Most cited references74

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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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              Circ-ZNF609 Is a Circular RNA that Can Be Translated and Functions in Myogenesis

              Summary Circular RNAs (circRNAs) constitute a family of transcripts with unique structures and still largely unknown functions. Their biogenesis, which proceeds via a back-splicing reaction, is fairly well characterized, whereas their role in the modulation of physiologically relevant processes is still unclear. Here we performed expression profiling of circRNAs during in vitro differentiation of murine and human myoblasts, and we identified conserved species regulated in myogenesis and altered in Duchenne muscular dystrophy. A high-content functional genomic screen allowed the study of their functional role in muscle differentiation. One of them, circ-ZNF609, resulted in specifically controlling myoblast proliferation. Circ-ZNF609 contains an open reading frame spanning from the start codon, in common with the linear transcript, and terminating at an in-frame STOP codon, created upon circularization. Circ-ZNF609 is associated with heavy polysomes, and it is translated into a protein in a splicing-dependent and cap-independent manner, providing an example of a protein-coding circRNA in eukaryotes.
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                Author and article information

                Contributors
                susana.santos@ineb.up.pt
                Journal
                Curr Osteoporos Rep
                Curr Osteoporos Rep
                Current Osteoporosis Reports
                Springer US (New York )
                1544-1873
                1544-2241
                29 April 2023
                29 April 2023
                2023
                : 21
                : 3
                : 289-302
                Affiliations
                [1 ]GRID grid.5808.5, ISNI 0000 0001 1503 7226, i3S – Instituto de Investigação e Inovação em Saúde, , Universidade do Porto, ; Porto, Portugal
                [2 ]GRID grid.5808.5, ISNI 0000 0001 1503 7226, INEB – Instituto de Engenharia Biomédica, , Universidade do Porto, ; Porto, Portugal
                [3 ]GRID grid.5808.5, ISNI 0000 0001 1503 7226, ICBAS – Instituto de Ciências Biomédicas Abel Salazar, , Universidade do Porto, ; Porto, Portugal
                Article
                786
                10.1007/s11914-023-00786-7
                10169890
                37119447
                5b81efb1-491e-404a-a35c-fa927e332a32
                © The Author(s) 2023

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 21 March 2023
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001871, Fundação para a Ciência e a Tecnologia;
                Award ID: SFRH/BD/147229/2019
                Award ID: CEECINST/00091/2018/CP1500/CT0011
                Award Recipient :
                Funded by: Universidade do Porto
                Categories
                Article
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2023

                Orthopedics
                transcriptome,osteogenic differentiation,osteoclastogenesis,bone
                Orthopedics
                transcriptome, osteogenic differentiation, osteoclastogenesis, bone

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