FTO-mediated m6A demethylation of pri-miR-3591 alleviates osteoarthritis progression

Arthritis Research & Therapy, Journal Year: 2023, Volume and Issue: 25(1)

Published: April 1, 2023

Abstract Objectives Increasing evidence have demonstrated the N6-methyladenosine (m 6 A) plays critical roles in osteoarthritis (OA) progression, but role of m A OA has not been completely illuminated. Herein, we investigated function and underlying mechanism demethylase fat mass obesity-associated protein ( FTO ) progression. Materials methods The expression was detected mice cartilage tissues lipopolysaccharide (LPS)-stimulated chondrocytes. Gain-of-function assays used to evaluate injury vitro vivo. miRNA-sequencing, RNA-binding immunoprecipitation (RIP), luciferase reporter assay, pri-miRNA processing were conducted confirm that modulated pri-miR-3591 process an m6A-dependent manner then binding sites miR-3591-5p with PRKAA2 . Results outstandingly downregulated LPS-stimulated chondrocytes tissues. overexpression enhanced proliferation, suppressed apoptosis, decreased degradation extracellular matrix LPS-induced chondrocytes, whereas knockdown contributed opposite effects. In vivo animal experiments showed markedly alleviated injury. Mechanically, -mediated m6A demethylation leaded a maturation block , which relieved inhibitory effect on promoted increase thereby alleviating damage. Conclusions Our results attested damage by mediating / axis, provided fresh insights into therapeutic strategies for OA.

Language: Английский

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Recent advances of m6A methylation in skeletal system disease

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: Feb. 14, 2024

Abstract Skeletal system disease (SSD) is defined as a class of chronic disorders skeletal with poor prognosis and causes heavy economic burden. m6A, methylation at the N6 position adenosine in RNA, reversible dynamic modification posttranscriptional mRNA. Evidences suggest that m6A modifications play crucial role regulating biological processes all kinds diseases, such malignancy. Recently studies have revealed most abundant epigentic modification, involved progression SSD. However, function SSD not fully illustrated. Therefore, make clear relationship between pathogenesis might provide novel sights for prevention targeted treatment This article will summarize recent advances regulation SSD, including osteoporosis, osteosarcoma, rheumatoid arthritis osteoarthritis, discuss potential clinical value, research challenge future prospect

Language: Английский

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m6A Regulator-Mediated RNA Methylation Modification Patterns Regulate the Immune Microenvironment in Osteoarthritis

Frontiers in Genetics, Journal Year: 2022, Volume and Issue: 13

Published: June 23, 2022

Epigenetic regulation, particularly RNA n6 methyl adenosine (m6A) modification, plays an important role in the immune response. However, regulatory of m6A microenvironment osteoarthritis (OA) remains unclear. Accordingly, we systematically studied modification patterns mediated by 23 regulators 38 samples and discussed characteristics modified m6A. Next, constructed a novel OA nomogram, m6A-transcription factor-miRNA network, drug network. Healthy showed distinct factor expression patterns. YTHDF3 was upregulated positively correlated with type II helper cells TGFb family member receptors. Furthermore, three different were factors; Mode 3, levels YTHDF3, T cells, receptors upregulated. Pathways related to endoplasmic reticulum oxidative stress mitochondrial autophagy strong correlation factors associated 3 factors. Through RT-qPCR validated that SREBF2 EGR1 as transcription IGF2BP3 are closely development OA, hsa-miR-340 miRNA for involved also detected protein IGF2BP3, western blotting, results consistent PCR. Overall, nomogram can facilitate prediction risk.

Language: Английский

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Regulatory Role of N6-Methyladenosine (m6A) Modification in Osteoarthritis

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 10

Published: June 30, 2022

Osteoarthritis (OA) is the most common joint disease, usually occurring in middle-aged and elderly people. However, current treatment for OA its early stages ineffective, drug therapy often ineffective slowing progression of disease. In fact, a deeper understanding underlying molecular mechanisms could help us to better develop effective therapeutic measures. N6-methyladenosine (m6A) methylation that occurs at adenosine N6-position, which internal modification on eukaryotic mRNAs. The role m6A mammalian gene regulation have been extensively studied. “Writer”, “eraser”, “reader” proteins are key involved dynamic modifications. Recent studies post-transcriptional alone shown m6a has an important development OA. This paper summarizes specific regulatory processes M6A disease reviews OA, describing pathophysiological mechanisms, as well future research trends potential clinical applications

Language: Английский

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Elucidating the role of ubiquitination and deubiquitination in osteoarthritis progression

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: June 9, 2023

Osteoarthritis is non-inflammatory degenerative joint arthritis, which exacerbates disability in elder persons. The molecular mechanisms of osteoarthritis are elusive. Ubiquitination, one type post-translational modifications, has been demonstrated to accelerate or ameliorate the development and progression via targeting specific proteins for ubiquitination determining protein stability localization. Ubiquitination process can be reversed by a class deubiquitinases deubiquitination. In this review, we summarize current knowledge regarding multifaceted role E3 ubiquitin ligases pathogenesis osteoarthritis. We also describe insight into processes. Moreover, highlight multiple compounds that target influence progression. discuss challenge future perspectives modulation expression enhancement therapeutic efficacy patients. conclude modulating deubiquitination could alleviate achieve better treatment outcomes

Language: Английский

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The regulatory role and mechanism of lncTUG1 on cartilage apoptosis and inflammation in osteoarthritis

Arthritis Research & Therapy, Journal Year: 2023, Volume and Issue: 25(1)

Published: June 20, 2023

Abstracts Background Long-stranded non-coding RNA TUG1 is lowly expressed in osteoarthritic chondrocytes. This study aimed to elucidate the role of cartilage damage and underlying mechanisms. Methods Combined database analysis, using primary chondrocytes as well C28/I2 cell line, was performed by qRT-PCR, Western blotting, immunofluorescence determine expression TUG1, miR-144-3p, DUSP1, other target proteins. Dual luciferase reporter gene RIP verify direct interaction with miR-144–3-p Annexin V-FITC/PI double staining detect apoptosis. CCK-8 proliferation. The biological significance DUSP1 assessed vitro experiments siRNA for mimic repressor overexpression plasmid DUSP1. In this study, all data were subjected a t -test or one-way analysis variance p -value < 0.05 cutoff. Results closely associated chondrocyte damage, knockdown significantly promoted apoptosis inflammation. present we found that inhibited inflammation competitively binding deregulating negative regulatory effect miR-144-3p on promoting expression, inhibiting p38 MAPK signaling pathway. Conclusions conclusion, our clarifies ceRNA network TUG1/miR-144-3p/DUSP1/P38 OA injury provides an experimental theoretical basis genetic engineering tools promote articular repair. Graphical abstract

Language: Английский

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M⁶A Demethyltransferase FTO Attenuates Meniscus Degeneration and Osteoarthritis via Orchestrating Autophagy and Energetic Metabolism

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Abstract Impaired autophagy is reported to promote osteoarthritis (OA). However, the mechanism by which in regulating meniscus degeneration and OA remains unclear. Here, unconvered aberrant energetic metabolism pattern cells with uncovered first, results lower adenosine triphosphate (ATP) production. And these phenomena are induced impaired OA. It further revealed that suppression of m 6 A demethylase fat mass obesity‐associated protein (FTO) inhibits causing ATP production reducing oxidative phosphorylation. Specific deletion FTO generating flox/flox ; COL1A1‐Cre ERT2 (FTO cko ) mice impair OA, while intra‐articular injection adeno‐associated virus (AAV‐FTO) restores alleviates Mechanistically, regulates mRNA stability ATG16L1 targeting methylation sites on a YTHDF2‐dependent manner, thereby inhibiting formation autophagosomes an imbalance metabolism. Intra‐articular AAV‐FTO reverses catabolic phenotype mice. In summary, findings reveal orchestrates A‐dependent manner. Therefore, might be potential therapeutic strategy for early‐stage

Language: Английский

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Therapeutic targets in aging-related osteoarthritis: A focus on the extracellular matrix homeostasis

Life Sciences, Journal Year: 2025, Volume and Issue: unknown, P. 123487 - 123487

Published: Feb. 1, 2025

Language: Английский

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From bone marrow mesenchymal stem cells to diseases: the crucial role of m6A methylation in orthopedics

Stem Cell Research & Therapy, Journal Year: 2025, Volume and Issue: 16(1)

Published: May 6, 2025

Elucidating the molecular mechanisms underlying orthopedic diseases is crucial for guiding therapeutic strategies and developing innovative interventions. N6-methyladenosine (m6A)-an epitranscriptomic modification-has emerged as a key regulator of cellular fate tissue homeostasis. Specifically, m6A plays pivotal role in several RNA biological processes such precursor splicing, 3'-end processing, nuclear export, translation, stability. Recent advancements indicate that methylation regulates stem cell proliferation osteogenic differentiation by modulating various signaling pathways. Extensive research has shown abnormalities contribute significantly to onset progression osteoporosis (OP), osteoarthritis (OA), rheumatoid arthritis (RA), bone tumors. This review aims summarize proteases involved their functions. The detailed which marrow mesenchymal cells (BMSCs) through direct indirect ways are also discussed, with focus on specific Finally, this analyzes roles modification development multiple diseases, offering comprehensive understanding pathophysiology these conditions proposing new directions targets treatment strategies.

Language: Английский

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Biological functions and applications of LncRNAs in the regulation of the extracellular matrix in osteoarthritis

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 11

Published: Jan. 8, 2024

Osteoarthritis (OA) is a major cause of disability, characterized by chronic pain, irreversible destruction, and loss function the articular cartilage. The integrity arrangement composition structure extracellular matrix (ECM) are essential for maintaining elasticity, integrity, mechanical support cartilage tissue. causes substantial changes in ECM, driving progression disease. Recent studies have shown that ECM plays critical role development tissue as well occurrence osteoarthritis directly or indirectly regulating chondrocyte proliferation, apoptosis, differentiation, gene expression. Long non-coding RNAs (lncRNAs) class derived from large transcripts. Mutations disorders lncRNAs closely related to osteoarthritis. Abnormal expression osteoarthritic regulates synthesis decomposition cartilaginous ECM. Therefore, use nucleic acid drugs regulate their targets may reduce degradation, thereby delaying pathological In this review, regulatory effects on different cell behaviors OA summarized. roles ECM-related activity chondrocytes, application potential therapy repair regeneration tissue, also reviewed. A better understanding guiding behavior metabolism future applications regenerative medicine.

Language: Английский

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