Circular RNAs: typical biomarkers for bone-related diseases

Circular RNAs: typical biomarkers for bone-related diseases 环状RNA：骨相关疾病的典型生物标志物 first-author corresp Jun ZOU, junzou@sus.edu.cn Jun ZOU, junzou@sus.edu.cn junzou@sus.edu.cn https://orcid.org/0000-0001-6036-8067 School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China 上海体育学院运动科学学院，中国上海，200438 上海体育学院运动科学学院，中国上海，200438 Bone is a connective tissue that has important functions in the human body. Cells and the extracellular matrix (ECM) are key components of bone and are closely related to bone-related diseases. However, the outcomes of conventional treatments for bone-related diseases are not promising, and hence it is necessary to elucidate the exact regulatory mechanisms of bone-related diseases and identify novel biomarkers for diagnosis and therapy. Circular RNAs (circRNAs) are single-stranded RNAs that form closed circular structures without a 5' cap or 3' tail and polycyclic adenylate tails. Due to their high stability, circRNAs have the potential to be typical biomarkers. Accumulating evidence suggests that circRNAs are involved in bone-related diseases, including osteoarthritis, osteoporosis, osteosarcoma, multiple myeloma, intervertebral disc degeneration, and rheumatoid arthritis. Herein, we summarize the recent research progress on the characteristics and functions of circRNAs, and highlight the regulatory mechanism of circRNAs in bone-related diseases. 骨是一种在人体中具有重要功能的结缔组织。细胞和细胞外基质（Extracellular matrix，ECM）是骨骼的关键组成部分，与骨相关疾病密切相关。然而，常规方法治疗骨相关疾病的结果并不乐观，因此需要通过阐明骨相关疾病的确切调控机制，寻找用于疾病诊断和治疗的新型生物标志物。环状RNA（Circular RNA，circRNA）是一种具有闭合环状结构的没有5’端或3’端多环腺苷酸尾的单链RNA。由于其高稳定性，circRNA有望成为典型的生物标志物。并且越来越多的证据表明circRNA参与调控骨相关疾病，包括骨关节炎、骨质疏松、骨肉瘤、多发性骨髓瘤、椎间盘退变和类风湿关节炎。本文综述了近年来circRNA特性和功能的研究进展，重点阐述了circRNA在骨相关疾病中的调控机制。 Circular RNA Bone-related disease Competing endogenous RNA (ceRNA) MicroRNA 环状RNA 骨相关疾病 ceRNA 微小RNA 1 Introduction 1 Bone as a connective tissue is a metabolic entity that performs its function by storing calcium and phosphate, regulating the acid-base balance and supporting hematopoiesis, thereby maintaining movement, support, and protection ( Buck and Dumanian, 2012 Buck and Dumanian, 2012 ; Florencio-Silva et al., 2015 Florencio-Silva et al., 2015 ). It mainly consists of cells and extracellular matrix (ECM). Osteoblasts, osteoclasts, osteocytes, and chondrocytes are the four major cell types that play significant roles in regulating bone homeostasis (del Fattore et al., 2012; Florencio-Silva et al., 2015 Florencio-Silva et al., 2015 ). Under the guidance of genetic and molecular factors and the local microenvironment, bone marrow mesenchymal stem cells (BMSCs) can differentiate into various mature cell types, including osteocytes, osteoblasts, and adipocytes ( Discher et al., 2009 Discher et al., 2009 ; Lopes et al., 2020 Lopes et al., 2020 ). The skeletal system is in a stable dynamic equilibrium, and its steady state relies on osteoblasts and osteoclasts that are responsible for bone formation and resorption. Osteocytes respond primarily to mechanical stimuli by transmitting signals to cells on the bone surface and adjusting the internal environment, while chondrocytes are mainly found on the surface of joints and play a role in cushioning and protection ( Blank and Sims, 2019 Blank and Sims, 2019 ; Ansari and Sims, 2020 Ansari and Sims, 2020 ) ( Fig. 1 Fig. 1 ). The imbalance of cells and ECM regulation leads to bone-related diseases that are difficult to cure completely, and impose a huge socioeconomic and medical burden. Therefore, there is an urgent need to elucidate the molecular regulatory mechanisms and search for new therapeutic targets for bone-related diseases. Circular RNAs (circRNAs) are a novel type of non-coding RNAs, which were originally thought to be viroids in plants ( Sanger et al., 1976 Sanger et al., 1976 ). However, with the development of high-throughput RNA sequencing and bioinformatics, circRNAs have been found to be widely distributed in many metazoans ( Salzman et al., 2012 Salzman et al., 2012 ; Memczak et al., 2013 Memczak et al., 2013 ). CircRNAs can be divided into four categories: exonic circRNAs (ecircRNAs) ( Chen et al., 2015 Chen et al., 2015 ), intronic circRNAs (ciRNAs) ( Zhang et al., 2018 Zhang et al., 2018 ), exon-intron circRNAs (EIciRNAs) ( Hsiao et al., 2017 Hsiao et al., 2017 ), and transfer RNA (tRNA) intronic circRNAs (tricRNAs) ( Geng et al., 2020 Geng et al., 2020 ). EIciRNAs and ciRNAs are mainly located in the nucleus, suggesting that they may be involved in gene expression ( Guo et al., 2014 Guo et al., 2014 ; Li et al., 2015 Li et al., 2015 ). ecircRNAs are the most abundant circRNAs and are found in the cytoplasm ( Jeck et al., 2013 Jeck et al., 2013 ) ( Fig. 2 Fig. 2 ). However, the study of circRNAs in disease is hampered by the limitations of experimental techniques and their own peculiar characteristics. In this review, we summarize the properties and functions of circRNAs and highlight their regulatory roles in osteosarcoma (OS), osteoarthritis (OA), osteoporosis (OP), multiple myeloma (MM), intervertebral disc degeneration (IDD), and rheumatoid arthritis (RA), to find evidence for the potential clinical value of circRNAs as molecular markers for the diagnosis and treatment of bone-related diseases. 2 Characteristics of circRNAs 1 CircRNAs, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) are all non-coding RNAs found mainly in the cytoplasm. Compared to lncRNAs, circRNAs are single-stranded RNAs that form a closed circular structure in which the 5' cap and 3' tail are connected, making the tissue more stable. They are resistant to RNA exonuclease-mediated degradation and may thus be ideal biomarkers for diagnosis or therapeutic targets ( Qu et al., 2015 Qu et al., 2015 ; Zhang et al., 2016 Zhang et al., 2016 ; Huang S et al., 2017 Huang S et al., 2017 ; Huang XQ et al., 2019 Huang XQ et al., 2019 ). CircRNAs are widely expressed in cell activity, embryonic development, neuronal development, and the pathogenesis of various diseases ( Guarnerio et al., 2016 Guarnerio et al., 2016 ; van Rossum et al., 2016 van Rossum et al., 2016 ), and are involved in diseases mainly by regulating cell differentiation, proliferation, migration, invasion, and inflammatory responses ( Wan et al., 2016 Wan et al., 2016 ; Luo et al., 2017 Luo et al., 2017 ; Tian et al., 2017 Tian et al., 2017 ; Yuan et al., 2019 Yuan et al., 2019 ). Numerous studies have shown that circRNAs can be expressed in a specific form in a variety of organisms ( Chen, 2016 Chen, 2016 ; Zhao et al., 2019 Zhao et al., 2019 ). The expression of circRNAs is tissue-specific. For example, circRNAs are enriched in the nervous system, especially when neurons are developing or undergoing apoptosis ( Venø et al., 2015 Venø et al., 2015 ; You et al., 2015 You et al., 2015 ). 3 Functions of circRNAs 1 The functions of circRNAs are directly related to their particular structure. Currently, relevant studies are mainly focused on four mechanisms of circRNAs: (1) They feature the abundance of miRNA-binding sites that can act as molecular sponges for miRNAs to counteract miRNA-mediated messenger RNA (mRNA) inhibition via the competing endogenous RNA (ceRNA) network ( Yu et al., 2019 Yu et al., 2019 ; Huang GQ et al., 2020 Huang GQ et al., 2020 ; Xu GY et al., 2020 Xu GY et al., 2020 ) ( Fig. 2 Fig. 2 a); (2) They can associate with RNA-binding proteins (RBPs) to regulate the post-transcriptional process and influence protein expression and function ( Holdt et al., 2016 Holdt et al., 2016 ; Zang et al., 2020 Zang et al., 2020 ) ( Fig. 2 Fig. 2 b); (3) They have high sensitivity and extracellular stability, so they can be detected in blood without cellular components, allowing circRNAs to be used as particular biomarkers for diseases ( Salzman, 2016 Salzman, 2016 ; Luo et al., 2018 Luo et al., 2018 ); (4) They can regulate the transcription and alternative splicing of parent genes ( Zhang et al., 2013 Zhang et al., 2013 ; Conn et al., 2017 Conn et al., 2017 ) ( Fig. 2 Fig. 2 c). 4 Biomarkers for diseases 1 Due to the unique structure of circRNAs and their resistance to ribonuclease R (RNase R), circRNAs have the potential to be biomarkers and therapeutic targets in diseases ( Jeck and Sharpless, 2014 Jeck and Sharpless, 2014 ). Thus far, extensive studies have demonstrated that circRNAs are ideal biomarkers and have been applied in clinical practice, such as in tuberculosis ( Yi et al., 2020 Yi et al., 2020 ), renal cell carcinoma ( Chen Q et al., 2020 Chen Q et al., 2020 ), stroke ( Zuo et al., 2020 Zuo et al., 2020 ), and chronic obstructive pulmonary disease ( Chen SF et al., 2020 Chen SF et al., 2020 ). Due to their stability and high expression in various diseases, circRNAs are currently the focus of research, significantly advancing the study of disease mechanisms. As bone-related diseases increasingly threaten human health, circRNAs can play important roles as biomarkers. 5 CircRNAs involved in osteoarthritis 1 OA, a chronic, progressive, and degenerative joint disease, is particularly common among people over 65 years of age ( Charlier et al., 2016 Charlier et al., 2016 ). Chondrocyte injury and apoptosis, chondrocyte ECM degradation, and mechanical damage to the joint are the three main factors for the occurrence of OA ( Wang TF et al., 2020 Wang TF et al., 2020 ). CircRNAs have a more stable structure, are tissue-specific, and can influence the development of OA. Thus, circRNAs are slowly emerging as a potential diagnostic biomarker and therapeutic target for OA. 5.1 CircRNA and ECM 2 The degradation process of the ECM is relatively complicated, with the circRNA-miRNA-mRNA network playing a significant role at the post-transcriptional level. CircTMBIM6 and matrix metallopeptidase-13 (MMP-13) were upregulated in interleukin-1β (IL-1β)- and tumor necrosis factor-‍‍α (TNF-‍‍α)‍-induced OA, while miRNA-27a (miR-27a) was downregulated. CircTMBIM6 functions as ceRNA to promote ECM degradation ( Bai et al., 2020 Bai et al., 2020 ). Wu et al. (2017) Wu et al. (2017) showed that hsa_circ_0005105 inhibited the transcriptional activity of miR-26a to enhance the expression of target nicotinamide phosphoribosyl transferase (NAMPT), while promoting the expression of MMP-13 and a disintegrin and metalloproteinase with thrombospondin motifs type 4 (ADAMTS-4), which affected ECM degradation. Compared to normal cartilage, 71 circRNAs were differentially expressed in OA, of which 16 circRNAs were upregulated and 55 circRNAs were downregulated ( Liu et al., 2016 Liu et al., 2016 ); circRNA chondrocyte extracellular matrix related (circCER) was upregulated in chondrocytes stimulated by IL-1 and TNF-‍α, and it sponged miR-136 to enhance the expression of MMP-13. The silencing of circCER may promote ECM formation by inhibiting MMP-13 expression. 5.2 CircRNA and chondrocytes 2 Chondrocytes are the only cells in cartilage that are tightly regulated to maintain a dynamic balance between proliferation and apoptosis, which controls the biosynthesis and degradation processes of the ECM under normal physiological conditions ( Sandell and Aigner, 2001 Sandell and Aigner, 2001 ). CircRNA-9119 was positively related to chondrocyte proliferation; circRNA-9119 and phosphatase and tensin homolog (PTEN) activation decreased cell apoptosis. In contrast, a miR-26a mimic induced cell apoptosis, and the circRNA-9119/miR-26a/PTEN axis was found to be an important regulatory mechanism in the treatment of OA ( Chen CJ et al., 2020 Chen CJ et al., 2020 ). PTEN also acts on other signaling pathways, but in a different role. It can inhibit the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway, which is the main pathway to promote cell survival, upregulate the levels of MMP‐13 and ADAMTS‐5, and downregulate the levels of aggrecan and collagen type II α1 chain (COL2A1) to promote cell apoptosis ( Yamada and Araki, 2001 Yamada and Araki, 2001 ; Zhou ZB et al., 2021 Zhou ZB et al., 2021 ). Yuan et al. (2021) Yuan et al. (2021) corroborated that circZNF652 was significantly upregulated in lipopolysaccharide (LPS)‍-induced OA and promoted the mRNA and protein levels of PTEN expression. Huang ZH et al. (2021) Huang ZH et al. (2021) revealed the interference with circRNA_0092516 when targeting the miR-337-3p/PTEN pathway to inhibit chondrocyte apoptosis. In addition, the circCDH13/miR‍‐‍296‍‐‍3p/PTEN pathway promoted chondrocyte apoptosis and suppressed proliferation ( Zhou ZB et al., 2021 Zhou ZB et al., 2021 ). Overall, these studies suggested that PTEN is a novel regulatory factor in chondrocyte proliferation and apoptosis. In the IL-‍1β‍-induced chondrocyte model, circRNAs are also involved in the development and progression of OA. CircSEC24A has been positively associated with apoptosis and inflammation; it can attenuate miR-142-5p to promote the expression of sex-determining region Y-box protein 5 (SOX5), thereby exacerbating chondrocyte injury ( Shi et al., 2022 Shi et al., 2022 ). Wang QS et al. (2021) Wang QS et al. (2021) showed that circ_0114876 promotes TNF receptor-associated factor 2 (TRAF2) expression by targeting miR-671 in OA tissue. The overexpression of TRAF2 could induce apoptosis and attenuate the effects of high miR-671 expression. Furthermore, the upregulation of circ_0001103 could alleviate the inflammatory response and reduce apoptosis. The circ_0001103/miR-375/silencing information regulator 2-related enzyme 1 (SIRT1) axis has been considered as an important potential mechanism for the treatment of OA ( Zhang M et al., 2021 Zhang M et al., 2021 ). 5.3 CircRNA and mechanical damage 2 The mechanical damage of cartilage tends to cause inflammation, which is one of the causes of OA. In the anterior cruciate ligament transection (ACLT) mouse model, silencing circSLC7A2 enhanced the inflammatory response by increasing the level of miR-4498 targeting tissue inhibitor of metalloproteinase 3 (TIMP3). The injection of circSLC7A2 into the knee joint can alleviate joint pain and suppress osteophyte formation, slowing the progression of OA ( Ni et al., 2021 Ni et al., 2021 ). Yao et al. (2021) Yao et al. (2021) also confirmed that circ-0083429 functions as an miR-346 sponge to facilitate Sma- and Mad-related protein 3 (SMAD3), and injecting it into the joint cavities of ACLT mice could alleviate the progression of OA. In addition, circCDK14 was downregulated in an ACLT rabbit model. Moreover, the injection of circCDK14 in vivo inhibited the expression of MMP-3 and MMP-13 promoted the expression of SOX9 and SMAD2 ( Shen et al., 2020 Shen et al., 2020 ). The activation of circCDK14/miR-125a-5p/SMAD2 pathway may be a novel therapy to cure OA. The surgical destabilization of the medial meniscus (DMM) can also cause OA. Zhou et al. (2019) Zhou et al. (2019) demonstrated that the knockdown of circRNA.33186 inhibited chondrocyte apoptosis in a DMM-induced OA model via the miR-127-5p/MMP-13 axis. CircDE4D is only slightly expressed in OA, and the intra-articular injection of circPDE4D into DMM mice can support cartilage repair. Mechanistically, circPDE4D directly interacts with miR-103a-3p to promote fibroblast growth factor 18 (FGF18) expression ( Wu et al., 2021 Wu et al., 2021 ). In summary, circRNA can exert its effects in ECM, chondrocytes, and inflammation to regulate the progression of OA, and thus may be a promising molecular targeted therapy for OA. The functions of circRNAs and related signaling pathways in OA are shown in Table S1. 6 CircRNAs involved in osteoporosis 1 OP is a common orthopaedic disease characterized by increased bone absorption and decreased bone formation ( Li et al., 2022 Li et al., 2022 ). The decrease in bone density and damage to its microstructure further increase the fragility of bone tissue, which results in a dramatic rise in the incidence of fractures ( Coughlan and Dockery, 2014 Coughlan and Dockery, 2014 ; Jin et al., 2018 Jin et al., 2018 ). In recent years, research into the pathogenesis of OP has continued to deepen. CircRNAs have been reported to influence the differentiation and function of osteoblasts ( Yu and Liu, 2019 Yu and Liu, 2019 ), osteoclasts ( Zhai et al., 2018 Zhai et al., 2018 ), and BMSCs ( Ren et al., 2019 Ren et al., 2019 ), and are involved in the regulation of bone metabolism (Table S2). Due to the unique ring structure of circRNAs, they have high stability, which makes them potentially useful in the treatment of OP. 6.1 CircRNAs and bone formation 2 Osteoblasts and BMSCs play vital roles in regulating the bone formation, which is tightly controlled by a variety of intracellular signaling pathways ( Yamaguchi et al., 2000 Yamaguchi et al., 2000 ); the role of circRNAs in osteoblast differentiation is currently the focus of research. In a study by Qian et al. (2017) Qian et al. (2017) , the expression levels of 158 circRNAs in bone morphogenetic protein-2 (BMP2)‍-induced MC3T3-E1 cells were found to be different from those in the control group. A total of 74 circRNAs were upregulated, the expression levels of circ19142 and circ5846 were significantly increased and 84 were downregulated, suggesting that circRNAs may be involved in the regulation of osteogenic differentiation. Mm9_circ_009056 was upregulated in MC3T3-E1 cells induced by calcitonin gene-related peptide (CGRP), while the expression of miR-22-3p was significantly decreased. The silencing of mm9_circ_009056 was able to increase the occurrence of miR-22-3p and decrease the expression levels of BMP7 and Runt-related transcription factor 2 (Runx2) ( Wu et al., 2018 Wu et al., 2018 ). In addition, Wnt/β‍-catenin was indicated as an important signaling pathway in osteoblasts and OP ( Xu ZH et al., 2020 Xu ZH et al., 2020 ). Circ_0024097 promoted the osteogenic differentiation of MC3T3-E1 cells by adsorbing miR-376b-3p as the ceRNA of Yes-associated protein 1 (YAP1) and activating the Wnt/β‍-catenin pathway ( Huang YX et al., 2020 Huang YX et al., 2020 ). In mesenchymal stem cells (MSCs), hsa_circ_0076906 combined with miR-1305 promoted the expression of osteoglycin (OGN), stimulating the differentiation of BMSCs into osteoblasts ( Wen J et al., 2020 Wen J et al., 2020 ). Li F et al. (2021) Li F et al. (2021) found that the overexpression of circ_0062582 can promote osteoblast differentiation and cell proliferation. Via targeting miR-145, it can affect the expression of core-binding factor subunit β (CBFB) in human BMSCs (hBMSCs). The above results demonstrate that circRNAs can promote osteogenic differentiation and thus prevent and treat OP. 6.2 CircRNAs and bone absorption 2 Osteoclasts are the only cell type that can absorb the bone matrix, and their excessive activation can lead to OP ( Chen et al., 2019 Chen et al., 2019 ). The differentiation of osteoclasts requires the induction of the receptor activator of nuclear factor-κB ligand (RANKL) and colony-stimulating factor 1 (CSF1). In this way, the expression of circRNA_28313 is upregulated. The change in circRNA_28313 expression was positively correlated with osteoclast differentiation, and miR-195a could bind circRNA_28313 and CSF1 to establish a ceRNA network that regulates bone absorption ( Chen et al., 2019 Chen et al., 2019 ). CircRNA_009934 is highly expressed during osteoclast differentiation and can bind miR-5107 to promote TNF receptor-associated factor 6 (TRAF6) expression ( Miao et al., 2020 Miao et al., 2020 ). TNF-‍α can decrease osteoblast differentiation and increase osteoclast activity ( David and Schett, 2010 David and Schett, 2010 ). Liu ZC et al. (2020) Liu ZC et al. (2020) demonstrated that circHmbox1 plays a role in TNF-‍‍α-induced osteoclasts. It could intercept miR-1247-5p to promote the expression of B-cell lymphoma 6 (Bcl6) to inhibit osteoclast differentiation, and when exosomes were secreted by osteoclasts that only slightly expressed circHmbox1, osteoblast differentiation was inhibited. Guan et al. (2021) Guan et al. (2021) found that hsa_circ_0021739 had lower expression in the OP group than in the control group. The overexpression of hsa_circ_0021739 may inhibit osteoclast differentiation via targeting hsa-miR-502-5p. Overall, data show that in the process of OP, circRNAs are involved in the regulation of osteoclasts. 7 CircRNAs involved in osteosarcoma 1 OS is the most prevalent primary malignant bone tumor that occurs mainly in children/adolescents and adults over 50 years of age ( Suehara et al., 2019 Suehara et al., 2019 ). It is highly invasive, metastasizes rapidly, and has a high mortality rate and poor prognosis ( Li SL et al., 2019 Li SL et al., 2019 ; Zhao et al., 2021 Zhao et al., 2021 ). OS initially affects the long bones and gradually involves other bones ( Zhang ZC et al., 2020 Zhang ZC et al., 2020 ). CircRNAs have been studied extensively in OS, and several researchers have conducted one specific circRNA, focusing on its regulatory role in OS reaching a certain level of maturity. Compared with the control group, hsa_circ_0000885 was highly expressed in the serum of OS and could be used as a potential biomarker for OS ( Zhu et al., 2019 Zhu et al., 2019 ). Chen YX et al. (2020) Chen YX et al. (2020) demonstrated the interaction among circ_0000885, miR-1249, and fibroblast growth factor receptor 1 (FGFR1) in OS by cell transfection. They found that circ_0000885 could target miR-1294 as an OS oncogene to promote FGFR1 expression and thus promoted OS progression. In the tissues and cells of OS, the overexpression of circ_0000285 was positively associated with insulin-like growth factor-binding protein 3 (IGFBP3), enhancing the migration and proliferation of OS through the circ_0000285/miR-409-3p/IGFBP3 axis ( Long et al., 2020 Long et al., 2020 ). Zhang ZC et al. (2020) Zhang ZC et al. (2020) verified that the other axis via hsa_circ_0000285 could bind miRNA-599 to promote the expression of transforming growth factor β2 (TGFB2). Furthermore, circUBAP2 was significantly increased in OS tissues compared to controls and might be involved in the regulation of OS via the activation of miR-143/Bcl2 axis ( Zhang et al., 2017 Zhang et al., 2017 ), miR-641/YAP1 axis ( Wu et al., 2020 Wu et al., 2020 ), miR‐204‐3p/high mobility group AT-hook 2 (HMGA2) axis ( Ma et al., 2021 Ma et al., 2021 ), and miR-506-3p/SEMA6D axis ( Dong and Qu, 2020 Dong and Qu, 2020 ). The activation of the above signaling pathways may regulate the progression of OS and contribute to the further elucidation of pathogenesis. However, the results of some circRNA studies need to be further confirmed. CircRNA itchy E3 ubiquitin protein ligase (circITCH) is a circRNA that is downregulated in OS tissues, and it suppresses OS progression through the circITCH/miR-524/RASSF6 axis ( Zhou W et al., 2021 Zhou W et al., 2021 ). However, Li et al. (2020) Li et al. (2020) revealed that circITCH was significantly upregulated in OS; silencing circITCH enhanced miR-7 expression and inhibited epidermal growth factor receptor (EGFR) expression. CircRNA homeodomain-interacting protein kinase 3 (circHIPK3) was associated with various cancers, and circHIPK3 expression may be a sign of accelerated cancer development ( Wen JY et al., 2020 Wen JY et al., 2020 ). CircHIPK3 is derived from exon2 of the HIPK3 gene and is a research hotspot in OS. It is a molecular sponge that competitively binds miRNA to exert its function ( Zhang YL et al., 2020 Zhang YL et al., 2020 ). Ma et al. (2018) Ma et al. (2018) first discovered that circHIPK3 had lower expression in OS cells and tissues than in the control group. The overexpression of circHIPK3 in vitro inhibits the development of OS, and hence it can be used as a biomarker for the treatment of OS. However, Huang ZY et al. (2020) Huang ZY et al. (2020) took the opposite view and found that circHIPK3 was obviously upregulated in OS cell lines and regulated signal transducer and activator of transcription 3 (STAT3) via miR-637, triggering the occurrence of OS. In another study, Wen Y et al. (2021) Wen Y et al. (2021) also showed that circHIPK3 was highly expressed in OS tissues and cells, and they argued that it exists in the cytoplasm; the circHIPK3 sponge miR-637 was found to positively regulate histone deacetylase 4 (HDAC4) expression, thus facilitating the proliferation, migration, and invasion of OS cells (Table S3). In conclusion, circRNAs with upregulated expression in OS have been studied extensively. Even though some studies are contradictory, the results suggest that circRNAs are important in the regulation of OS. With the further understanding of circRNA and advances in experimental technology, more studies are expected to verify this notion. 8 CircRNAs involved in multiple myeloma 1 MM is a hematological malignancy caused by plasma cells that proliferate abnormally in the bone marrow, and by the abundant secretion of monoclonal immunoglobins ( Huang H et al., 2020 Huang H et al., 2020 ; Luo and Gui, 2020 Luo and Gui, 2020 ; Zhou et al., 2020 Zhou et al., 2020 ). Although bortezomib (BTZ) has shown a good clinical effect and is widely used, some patients are not eligible for it ( Fu et al., 2019 Fu et al., 2019 ). Therefore, the search for novel biomarkers is crucial for the diagnosis and targeted treatment of MM. CircRNAs are novel biomarkers for the regulation of MM; hsa_circRNA_101237 ( Liu X et al., 2020 Liu X et al., 2020 ), hsa_circ_0007841 ( Gao et al., 2019 Gao et al., 2019 ), and hsa_circ_0069767 ( Chen F et al., 2020b Chen F et al., 2020b ) were all significantly upregulated in MM. Using cell models with the overexpression or knockdown of circ_0069767, Chen F et al. (2020b) Chen F et al. (2020b) demonstrated that overexpressed hsa_circ_0069767 can promote cell apoptosis and that knocking down hsa_circ_0069767 increases proliferation, migration, and invasion. Circ_0007841 is a research hotspot, and several studies have shown that it can regulate the process of MM via the hsa_circ_0007841/adenosine triphosphate (ATP)‍-binding cassette transporters G2 (ABCG2) ( Song et al., 2020 Song et al., 2020 ), circ_0007841/miR-338-3p/bromodomain-containing 4 (BRD4) ( Wang Y et al., 2020a Wang Y et al., 2020a ), and circ_0007841/miR-129-5p/Jagged1 (JAG1) ( Wang Y et al., 2020b Wang Y et al., 2020b ) signaling pathways. CircRNA chromodomain Y-like (circCDYL) and circ_0000142 exacerbated the progression of MM by activating the circCDYL/miR-1180/YAP axis ( Chen F et al., 2020a Chen F et al., 2020a ) and circ_0000142/miR-610/RAC-γ serine/threonine-protein kinase (AKT3) axis ( Liu et al., 2021 Liu et al., 2021 ). However, circRNAs were also involved in MM. Circ_0000190 was downregulated in tissues of MM and peripheral blood, and it can intercept miR-767-5p to enhance mitogen-activated protein kinase 4 (MAPK4) expression, to inhibit the growth and progression of MM ( Feng et al., 2019 Feng et al., 2019 ). BTZ is a typical chemotherapeutic drug in MM, but BTZ chemoresistance is a challenge to be solved ( Gonzalez-Santamarta et al., 2020 Gonzalez-Santamarta et al., 2020 ). Fang et al. (2021) Fang et al. (2021) showed that the knockdown of circRNA arginine-glutamic acid dipeptide repeats (circRERE) attenuated BTZ chemoresistance, with circRERE acting mechanically through the miR-152-3p/cluster of differentiation 47 (CD47) axis. In contrast, the overexpression of circITCH can block BTZ resistance in MM. Moreover, circITCH binds miR-615-3p to upregulate protein kinase C-‍δ (PRKCD), thereby increasing BTZ sensitivity ( Liu JH et al., 2020 Liu JH et al., 2020 ) (Table S4). 9 CircRNAs involved in intervertebral disc degeneration 1 Cells of the nucleus pulposus (NP) can secret ECM to maintain the homeostasis of intervertebral discs. The aberrant function of NP cells will lead to IDD through three main mechanisms, namely cell senescence, apoptosis, and ECM degradation ( Li Z et al., 2019 Li Z et al., 2019 ; Chang et al., 2021 Chang et al., 2021 ). The IDD of the lumbar spine is closely associated with low back pain, which severely affects patients’ quality of life and increases the economic burden on society ( Xu GY et al., 2020 Xu GY et al., 2020 ). CircRNAs are crucial transcription regulatory factors in IDD. CircRNAs are capable to simultaneously regulate cell apoptosis and ECM degradation. Silencing circRNA glucuronic acid epimerase (circGLCE) could enhance the apoptosis of NP cells and matrix-degrading enzyme expression, and overexpression of circGLCE inhibited miR-587 to increase signal-transducing adaptor family member 1 (STAP1) expression ( Chen ZH et al., 2020 Chen ZH et al., 2020 ). In this respect, circGLCE acts as a therapeutic target for IDD via the miR-587/STAP1 axis. CircRNA involved in compression-induced damage of NP cells (circRNA-CIDN) is a negative regulator of IDD, as it promoted the expression of SIRT1 by targeting miR-34a-5p in loading-induced NP cells to slow the onset of IDD ( Xiang et al., 2020 Xiang et al., 2020 ). However, Cui and Zhang (2020) Cui and Zhang (2020) revealed that circ_001653 was positively related to the severity of IDD, and may serve as a sponge for miR-486-3p to upregulate cell migration-inducing protein (CEMIP) expression. Therefore, it can be regarded as a promising diagnostic biomarker for IDD. Currently, an increasing pool of researches have evidenced that circRNAs are widely involved in the regulation of IDD, and most of them involved circRNAs that are downregulated in IDD. CircRNA derived from vacuolar ATPase assembly factor 21 (circ-VMA21) ( Cheng et al., 2018 Cheng et al., 2018 ), circRNA PBX/knotted 1 homeobox 1 (circPKNOX1) ( Huang YZ et al., 2021 Huang YZ et al., 2021 ), circRNA growth factor receptor bound protein 10 (circGRB10) ( Guo et al., 2020b Guo et al., 2020b ), hsa_circ_0059955 ( Kong et al., 2020 Kong et al., 2020 ), circRNA ADP ribosylation factor-like GTPase 15 (circARL15) ( Wang HB et al., 2021 Wang HB et al., 2021 ), circRNA semaphorin 4B (circSEMA4B) ( Wang et al., 2018 Wang et al., 2018 ), and circRNA ERCC excision repair 2 (circERCC2) ( Xie et al., 2019 Xie et al., 2019 ) all notably ameliorated the progression of IDD by inhibiting cell apoptosis and ECM degradation. All of them could establish a ceRNA network that mediates the regulation of IDD, such as circPKNOX1/miR-370-3p/KIAA0355 ( Huang YZ et al., 2021 Huang YZ et al., 2021 ), circARL15/miR-431-5p/disrupted in schizophrenia 1 (DISC1) ( Wang HB et al., 2021 Wang HB et al., 2021 ), and circERCC2/miR-182-5p/SIRT1 ( Xie et al., 2019 Xie et al., 2019 ). Nevertheless, there are also upregulated circRNAs in IDD. For instance, Li YJ et al. (2021) Li YJ et al. (2021) demonstrated that circRNA family with sequence similarity 169 member A (circFAM169A) was overexpressed in degenerative NP tissues, while miR-583 was negatively related to circFAM169A and SOX9. Another study suggested that β‍-transducin repeat-containing E3 ubiquitin protein ligase ( BTRC ) is also the target gene of miR-583, and that the circFAM169A/miR-583/BTRC pathway is a therapeutic option for IDD ( Guo et al., 2020a Guo et al., 2020a ). CircRNA_104670 and circITCH modulated the progression of IDD via the miRNA-17-3p/MMP-2 axis and the miR-17-5p/SOX4 axis ( Song et al., 2018 Song et al., 2018 ; Zhang F et al., 2021 Zhang F et al., 2021 ), respectively (Table S5). 10 CircRNAs involved in rheumatoid arthritis 1 RA is a chronic systemic autoimmune disease with synovial hyperplasia, cartilage destruction, and bone erosion, leading to systemic inflammatory response ( Bombardieri et al., 2011 Bombardieri et al., 2011 ; Zheng et al., 2017 Zheng et al., 2017 ; Taheri et al., 2020 Taheri et al., 2020 ). Approximately 1% of the global population is affected by RA, while the pathogenesis and etiology of RA remain elusive ( Nemtsova et al., 2019 Nemtsova et al., 2019 ). In recent years, studies have gradually focused on the biomarkers of circRNAs in RA ( Wen JT et al., 2021 Wen JT et al., 2021 ). Two studies have explored the mechanisms of circRNA fragile mental retardation 2 (circAFF2) in RA tissues. CircAFF2 has a high expression level in RA fibroblast-like synoviocytes (RAFLSs). The increased expression of circAFF2 can enhance the proliferation, inflammatory response, and migration of RAFLSs. However, upregulated miR-650 reversed circAFF2-mediated effects in RA. 2',3'-Cyclic nucleotide 3'-phosphodiesterase ( CNP ) was the target gene of miR-650 ( Qu et al., 2021 Qu et al., 2021 ). Another study showed that circAFF2 exacerbated the extent of RA via the miR-375/TAK1-binding 2 (TAB2) axis ( Zhi et al., 2021 Zhi et al., 2021 ). CircPTPN22, hsa_circ_0002715, hsa_circ_0035197, and hsa_circ_0044235 in peripheral blood mononuclear cells have been identified as novel biomarkers for the diagnosis and treatment of RA ( Luo et al., 2018 Luo et al., 2018 , 2019 2019 ; Jiang et al., 2021 Jiang et al., 2021 ), while the relevant regulatory mechanisms need further investigation. Furthermore, Cai et al. (2021) Cai et al. (2021) demonstrated that circ_0088194 was upregulated in RAFLSs and bound to miR-766-3p. MMP-2 was positively related to circ_0088194, which promoted the migration and invasion of RAFLSs. The overexpression of miR-766-3p alleviated the promoting effect of circ_0088194, and MMP-2 expression was also inhibited. In addition, circRNA absent-small-homeotic-2-like protein (circASH2L), circMAPK9, and hsa_circ_0088036 were involved in promoting the growth and inflammation of RAFLSs by regulating the miR-129-5p/homeodomain-interacting protein kinase 2 (HIPK2) axis ( Li X et al., 2021 Li X et al., 2021 ), miR-140-3p/protein phosphatase magnesium-dependent 1A (PPM1A) axis ( Luo et al., 2021 Luo et al., 2021 ), and miR-140-3p/SIRT1 axis ( Zhong et al., 2020 Zhong et al., 2020 ), respectively (Table S6). 11 Conclusions 1 Bones are fundamental parts of the body with vital functions; the occurrence of bone-related diseases places a great burden on society. CircRNAs were demonstrated to act as molecular regulators of bone-related diseases and closely associated with disease development and severity. Although our understanding of circRNAs is still at the preliminary stage, we believe that circRNAs have good prospects as targets in disease regulation. The different expression of circRNAs between control and diseased groups indicates that they are involved in disease occurrence. Due to their high specificity and stability, circRNAs could be used as biomarkers for bone-related diseases. The fact that the overexpression or knockdown of circRNAs can influence the expression of mRNAs by sponging miRNAs and thus alleviate the disease process confirms that circRNAs can act as therapeutic targets. Currently, circRNAs are a relatively new subject of research. Due to their unique and stable structure, they are involved in the regulation of a variety of diseases. 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Stroke , 51 ( 1 ): 319 - 323 . https://doi.org/10.1161/strokeaha.119.027348 https://doi.org/10.1161/strokeaha.119.027348 Circulating circular RNAs as biomarkers for the diagnosis and prediction of outcomes in acute ischemic stroke Linghui HU: study development, data curation, writing ‍– original draft, writing ‍–‍ review and editing. Wei WU: writing ‍– review and editing. Jun ZOU: funding acquisition, supervision, writing ‍‍–‍ review and editing. All authors have read and approved the final manuscript. This work was supported by the National Natural Science Foundation of China (No. 81871835), the Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, and the Shanghai Key Lab of Human Performance (Shanghai University of Sport) (No. 11DZ2261100), China. 10.1631/jzus.B2200211 1673-1581（2022）12-0975-14 This work was supported by the National Natural Science Foundation of China (No. 81871835), the Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, and the Shanghai Key Lab of Human Performance (Shanghai University of Sport) (No. 11DZ2261100), China. 2022-04-11 2022-08-11 2022-12-15 2022-12-27 2022-10-31 Copyright © Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2022 2022 浙江大学出版社 Linghui HU, Wei WU, and Jun ZOU declare that they have no conflict of interest. This review does not contain any studies with human or animal subjects performed by any of the authors. Compliance with ethics guidelines Supplementary information 1 Tables S1‒S6 浙江大学学报（英文版）（B辑：生物医学和生物技术） 12 23