Search

Osteoarthritis (OA) is the most common joint disease with high prevalence and incidence. Increasing reports has indicated that circular RNAs (circRNAs) are implicated in OA progression. Nevertheless, the roles and functions of most circRNAs in OA remain to be elucidated. In this study, we emphatically discussed circ-IQGAP1 (circ_0104873) in OA. Firstly, we discovered that circ_0104873 was dramatically overexpressed during osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Several functional assays demonstrated that circ_0104873 inhibition repressed BMSCs proliferation and osteogenic differentiation. Moreover, mechanism assays also revealed that circ_0104873 sponged microRNA-875-5p (miR-875-5p) to up-regulate notch receptor 3 (NOTCH3), thereby activating the Notch signaling pathway. Rescue assays disclosed that circ_0104873 contributed to the development of OA via targeting miR-875-5p/NOTCH3 axis. In conclusion, circ_0104873 promoted the progression of OA by miR-875-5p/NOTCH3/Notch signaling pathway, which might provide a promising target for OA treatment., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Articular cartilage defects (ACD) are injuries with a diameter greater than 3 mm, resulting from wear and tear on joints. When the diameter of the defect exceeds 6 mm, it can further damage the surrounding joint cartilage, causing osteoarthritis (OA). Try to explain why OA is an irreversible disease, we hypothesize that damaged articular chondrocytes (DAC) may have reduced capacities to repair cartilage because its extracellular vesicle (EVs) that might directly contribute to OA formation., Methods: In this study, DAC-EVs and AC-EVs were isolated using ultracentrifugation. Next-generation sequencing was employed to screen for a pathogenic long non-coding RNA (lncRNA). After verifying its function in vitro, the corresponding small interfering RNA (siRNA) was constructed and loaded into extracellular vesicles, which were then injected into the knee joint cavities of rats., Results: The results revealed that DAC-EVs packaged lncRNA LOC102546541 acts as a competitive endogenous RNA (ceRNA) of MMP13, down-regulating miR-632. Consequently, the function of MMP13 in degrading the extracellular matrix is enhanced, promoting the development of osteoarthritis., Conclusions: This study uncovered a novel mode of OA pathogenesis using rat models, which DAC deliver pathogenic LOC102546541 packaged EVs to normal articular chondrocytes, amplifying the degradation of the extracellular matrix. Nonetheless, the functions of highly homologous human gene of LOC102546541 need to be verified in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Rotator cuff tear (RCT) is a common shoulder disorder related to pain and dysfunction. However, the pathological mechanism of RCT remains unclear. Thus, this study aims to investigate the molecular events in RCT synovium and identify possible target genes and pathways as determined by RNA sequencing (RNA-Seq). The synovial tissue was biopsied from 3 patients with RCT (RCT group) and 3 patients with shoulder instability (Control group) during arthroscopic surgery. Then, differentially expressed (DE) mRNAs, long non-coding RNAs (lncRNAs) and micro RNAs (miRNAs) were comprehensively profiled by RNA-Seq. Gene ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and competing endogenous RNA (ceRNA) network analysis were performed to identify the potential functions of these DE genes. 447 mRNAs, 103 lncRNAs and 15 miRNAs were identified differentially expressed. The DE mRNAs were highlighted in inflammatory pathway including up-regulated T cell costimulation, positive regulation of T cell activation, and T cell receptor signaling. Down-regulated fatty acid degradation pathway and 5'-AMP-activated protein kinase (AMPK) signaling in RCT group are also enriched. Validation assay showed that the expression of pro-inflammatory molecules including IL21R, CCR5, TNFSF11, and MMP11 was significantly increased in RCT group compared with Control group. CeRNA analysis further revealed lncRNA-miRNA-mRNA regulatory networks involving IL21R and TNFSF11 in RCT. Activated synovial inflammation is the remarkable event of RCT. Importantly, increased T cell activation and disordered fatty acid metabolism signaling might play a significant role. ceRNA networks involving IL21R and TNFSF11 identified could potentially control the progression of RCT. In conclusion, our findings could provide new evidence for the molecular mechanisms of RCT and might identify new therapeutic targets., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Whether long non-coding RNA Mir-99a-Let-7c Cluster Host Gene (LncRNA MIR99AHG) is involved in osteoporosis (OP) remains vague, so we hereby center on its implication. Old C57BL/6J mice were injected with the silencing lentivirus of MIR99AHG and subjected to microCT analysis and immunohistochemistry on osteogenic cells. The osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) with or without transfection was determined by alkaline phosphatase (ALP) and Alizarin Red S staining. Total N(6)-methyladenosine (m 6 A) on the bone marrow mesenchymal stem cells (BMSCs) was quantified. The potential methylation site and the complementary binding sites with candidate microRNA (miR) were predicted via bioinformatic analyses, with the latter being confirmed via dual-luciferase reporter, RNA immunoprecipitation and RNA pull-down assays. Quantitative real-time PCR and Western blot were used for quantification assays. MIR99AHG was decreased during the osteogenic differentiation of BMSCs, where increased Osterix (OSX), Collagen, Type I, Alpha 1 (Col1A1), Osteocalcin (OCN) and RUNX Family Transcription Factor 2 (RUNX2) as well as more color-stained areas were found. Also, silencing MIR99AHG relieved the OP in mice and reduced the loss of osteogenic cells. M 6 A methylation in undifferentiated BMSCs was low and MIR99AHG overexpression abolished the effects of overexpressed METTL3 on promoting osteogenic differentiation. MiR-4660, which was downregulated in BMSCs without differentiation but increased during osteogenic differentiation, could bind with MIR99AHG. Furthermore, miR-4660 promoted osteogenic differentiation and reversed the effects of overexpressed MIR99AHG. The present study demonstrated that METTL3-mediated LncRNA MIR99AHG methylation enhanced the osteogenic differentiation of BMSCs via targeting miR-4660.

Impaired osteoblast function is involved in osteoporosis, and microRNA (miRNA) dysregulation may cause abnormal osteoblast osteogenic activity. However, the influence of miRNA on osteoblast activity and the underlying mechanisms remain elusive. In this study, miR-103-3p was found to be negatively correlated with bone formation in bone specimens from elderly women with fractures and ovariectomized (OVX) mice. Additionally, miR-103-3p directly targeted Mettl14 to inhibit osteoblast activity, and METTL14-dependent N 6 -methyladenosine (m 6 A) methylation inhibited miR-103-3p processing by the microprocessor protein DGCR8 and promoted osteoblast activity. Moreover, miR-103-3p inhibited bone formation in vivo, and therapeutic inhibition of miR-103-3p counteracted the decreased bone formation in OVX mice. Further, METTL14 was negatively correlated with miR-103-3p but positively correlated with bone formation in bone specimens from elderly women with fractures and OVX mice. Collectively, our results highlight the critical roles of the miR-103-3p/METTL14/m 6 A signaling axis in osteoblast activity, identifying this axis as a potential target for ameliorating osteoporosis., (© 2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Impaired osteoblast proliferation plays fundamental roles in microgravity-induced bone loss, and cell cycle imbalance may result in abnormal osteoblast proliferation. However, whether microgravity exerts an influence on the cell cycle in osteoblasts or what mechanisms may underlie such an effect remains to be fully elucidated. Herein, we confirmed that simulated microgravity inhibits osteoblast proliferation. Then, we investigated the effect of mechanical unloading on the osteoblast cell cycle and found that simulated microgravity arrested the osteoblast cell cycle in the G 2 phase. In addition, our data showed that cell cycle arrest in osteoblasts from simulated microgravity was mainly because of decreased cyclin B1 expression. Furthermore, miR-181c-5p directly inhibited cyclin B1 protein translation by binding to a target site in the 3'UTR. Lastly, we demonstrated that inhibition of miR-181c-5p partially counteracted cell cycle arrest and decreased the osteoblast proliferation induced by simulated microgravity. In conclusion, our study demonstrates that simulated microgravity inhibits cell proliferation and induces cell cycle arrest in the G 2 phase in primary mouse osteoblasts partially through the miR-181c-5p/cyclin B1 pathway. This work may provide a novel mechanism of microgravity-induced detrimental effects on osteoblasts and offer a new avenue to further investigate bone loss induced by mechanical unloading., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Osteoarthritis (OA) is one of the most common chronic joint disease. Long non-coding RNAs (lncRNAs) have been confirmed to play important roles in a variety of diseases including OA. However, the underlying mechanism of lncRNA differentiation antagonizing non-protein coding RNA (DANCR) in OA has not been well elucidated. The expression of DANCR in cartilage tissues from OA patients was detected using quantitative real-time PCR. After cell transfection, the effects of DANCR inhibition on the proliferation, apoptosis and inflammatory factors of OA chondrocytes were detected using Cell Counting Kit-8 assay and flow cytometry assay. Novel target of DANCR was then identified through bioinformatics analysis and confirmed by luciferase reporter assay and RNA immunoprecipitation assay. The expression of DANCR was significantly increased in OA patients. Function assays demonstrated that DANCR suppression inhibited the proliferation, inflammation, and promoted apoptosis of chondrocytes cells. Additionally, DANCR regulated survival of OA chondrocytes through acting as a competitive endogenous RNA for miR-216a-5p. Furthermore, JAK2 was a direct target of miR-216a-5p, and DANCR regulated the JAK2/STAT3 signal pathway through miR-216a-5p in OA chondrocytes. In the present study, we concluded that DANCR promoted the proliferation, inflammation, and reduced cell apoptosis in OA chondrocytes through regulating miR-216a-5p/JAK2/STAT3 signaling pathway, indicating DANCR might be a useful biomarker and potential therapeutic target for OA treatment., (© 2018 The Author(s).)

Background/aims: MicroRNAs (miRNAs) have been reported to be involved in Rheumatoid arthritis (RA) pathogenesis and prognosis. However, little is known about the disease mechanism in RA. Here, we aim to investigate the potential association between miR-338-5p and NFAT5 in RA., Methods: Aberrant expression of miR-338-5p in RA tissues and rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs) compared to the normal were determined by RT-qPCR. Cell viability was determined using the CCK-8 assay, and cell apoptosis was analyzed via Annexin V-FITC/PI double staining and was detected using flow cytometry. The targeted relationship was determined by TargetScan database and dual luciferase reporter gene assay., Results: Upregulation of miR-338-5p facilitated the proliferation, migration, invasion and induced G0/G1 arrest of RAFLSs while miR-338-5p inhibitor functioned oppositely. Nuclear factor of activated T-cells 5 (NFAT5) was confirmed as a downstream target of miR-338-5p which expression was directly suppressed by miR-338-5p. Overexpression of NFAT5 attenuated the proliferation and metastasis of RAFLSs and those changes could be rescued by co-transfection of miR-338-5p., Conclusion: miR-338-5p promotes RAFLS's viability and proliferation, migration by targeting NFAT5, suggesting a novel therapeutic strategy for RA., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

miRNAs have been reported to regulate cellular differentiation by modulating multiple signaling pathways. Long noncoding RNA (lnc RNA) DANCR was previously identified to be critical for the chondrogenesis of human synovium-derived mesenchymal stem cells (SMSC), however, the underlying molecular mechanism requires better understanding. Here, miRNA expression profiling in DANCR overexpressed in SMSCs identified significant down-regulation of miR-1305 , which serves as a downstream target of DANCR. Notably, miR-1305 overexpression reversed DANCR-induced cell proliferation and chondrogenic differentiation of SMSCs, which suggested that miR-1305 antagonized the function of DANCR. Mechanistically, highly expressed miR-1305 resulted in the decreased expression of the TGF-β pathway member Smad4, and inhibition of miR-1305 enhanced the expression level of Smad4. Depletion of Smad4 suppressed the promotion of DANCR in cell proliferation and chondrogenesis of SMSCs. Collectively, our results characterized miR-1305 -Smad4 axis as a major downstream functional mechanism of lncRNA DANCR in promoting the chondrogenesis in SMSCs., (© 2017 The Author(s).)

The molecular regulation of the invasion of osteosarcoma (OS) remains elusive. Here, we reported significant lower level of miR-143 and significant levels of phosphorylated EGFR and MMP9 in the resected OS from the patients, compared to the adjacent normal tissue. Moreover, strong correlation was detected among these three factors. We thus hypothesized existence of a causal link, which prompted us to use two human OS cell lines to study the interaction of miR-143, MMP9, and activation of EGFR signaling. We found that EGF-induced EGFR phosphorylation in both lines activated MMP9, and consequently cancer invasiveness. Both an inhibitor for EGFR phosphorylation and an inhibitor for ERK1/2 phosphorylation significantly inhibited the EGF-induced activation of MMP9. Moreover, miR-143 levels did not alter by EGF-induced EGFR phosphorylation, while overexpression of miR-143 antagonized EGF-induced MMP9 activation without affecting EGFR phosphorylation. Taken together, our data suggest that miR-143 inhibits EGFR signaling through its downstream ERK/MAPK signaling cascades to control MMP9 expression in OS. Thus, miR-143, EGFR, and MMP9 are therapeutic targets for inhibiting OS invasion.

Osteosarcoma is the most common primary bone tumor. Recent data indicated miRNAs may be involved in the pathogenesis of osteosarcoma, suggesting some novel targets for therapy. It is known that miR-429 is down-regulated and functions as a tumor suppressor by targeting c-myc and PLGG1 in gastric and breast cancer. However, the exact role of miR-429 in osteosarcoma remained unknown. In our study, we found MiR-429 was down-regulated in primary osteosarcoma lesion and osteosarcoma cell lines. Moreover, MiR-429 can inhibit the proliferation of osteosarcoma cell lines and induce more cell apoptosis. Also, we discovered MiR-429 plays a role in osteosarcoma by binding the 3'UTR of zinc finger E-box-binding homeobox 1 (ZEB1) mRNA, and that overexpression of ZEB1 could reverse the proliferation, subsequently blocking effect of miR-429. In conclusion, miR-429 serves as a tumor suppressor via interaction with ZEB1. Our finding may provide a new target for osteosarcoma therapy.

Osteosarcoma is the most common primary malignancy to arise from bone. The pathogenesis of osteosarcoma is unclear, and new therapy molecular target is needed. The miRNAs researched suggested that miRNAs are involved in the pathogenesis of osteosarcoma. MiR-141, which belong to miR-200 family, take a part in tumorigenesis. However, the role of miR-141 in the pathogenesis of osteosarcoma remained unclear. In this study, we focused on the miR-141 in osteosarcoma and found that the expression of miR-141 is lower in osteosarcoma. Overexpression of miR-141 not only inhibits osteosarcoma cell proliferation but also induces cell apoptosis. It is estimated that miR-141 played its role via ZEB1 and ZEB2. In all, miR-141 played a osteosarcoma-suppressing role via ZEB1 and ZEB2. Our finding may elucidate the miRNAs mechanism in osteosarcoma and provide a new molecule target for osteosarcoma therapy.

Osteosarcoma is the 3rd most common human cancer in childhood and young adults, and is the leading cause of mortality. Recent studies suggest that miRNAs could regulate the growth and progression of osteosarcoma, indicating some novel targets for therapy. In our study, we demonstrated that miR-451 was down-regulated in human osteosarcoma U2OS, SAOS, and MG63 cells lines as well as in tumor tissue surgically resected compared with the normal tissues. Overexpression of miR-451 inhibited cell proliferation and resulted in cell apoptosis in osteosarcoma cells. G1 cell cycle arrest was also induced by miR-451. Repressed by miR-451, PGE2 and CCND1 reversed the inhibitory effects of miR-451 on proliferation. In conclusion, miR-451 played a tumor-suppressing role through modulating the expression of PGE2 and CCND1, suggesting a novel target for the diagnosis and treatment of osteosarcoma.

Background: Osteosarcoma is the most common primary bone malignancy in children and young adults. Most failures of osteosarcoma treatment were due to resistance to chemotherapy. Development of new therapy required elucidation underlying molecular mechanism. Many miRNAs have been proved to be involved in the pathogenesis of osteosarcoma., Methods: MiR-3928 expression level was assayed by qRT-PCR. MiRNA mimics or ASO were transfected for up-regulation or down-regulation of miR-3928 expression. Cell proliferation was assayed by formazan test. Apoptosis and cell cycle were assayed by FACS. MiR-3928 targeted genes were predicated by bioinformatics algorithm (TargetScanHuman). The correlation between targeted gene and miR-3928 was analyzed by Pearson's correlation coefficient analysis., Results: MiR-3928 was down-regulated in osteosarcoma tissues. Over-expression of miR-3928 inhibited tumor growth, induced cell apoptosis, increased the percent of cells in G1 phrase and decreased the percent of cells in S phrase. Down-regulation of miR-3928 promoted cell proliferation. ERBB3, IL-6R and CDK6 may be the targeted genes of miR-3928., Conclusions: Down-expression of miR-3928 in osteosarcoma promoted tumor growth by targeting ERBB3, IL-6R and CDK6. MiR-3928 may be a potential therapy target worth further investigation., (© 2014 S. Karger AG, Basel.)

Osteosarcoma is a primary malignant bone tumour with high morbidity that occurs mainly in children and adolescents. While the molecular basis of osteosarcoma has received considerable attention, the cellular and molecular mechanisms underlying pre- and postoperative metastasis formation and the development of chemoresistance remain unclear. MicroRNAs (miRNAs), a class of 22-nucleotide noncoding RNAs, have emerged as critical components of gene-regulatory networks controlling numerous important pathophysiological processes, including the initiation and progression of cancers. Studies on miRNAs have opened new avenues for both the diagnosis and treatment of cancer. This review discusses the roles of miRNAs in osteosarcoma and their potential applications for the diagnosis, prognosis and treatment of this malignancy. As a rapidly evolving field of basic and biomedical science, miRNA research will have a revolutionary impact on the management of osteosarcoma.