METTL3-mediated m6A modification increases Hspa1a stability to inhibit osteoblast aging

Cell Death Discovery, Год журнала: 2024, Номер 10(1)

Опубликована: Март 27, 2024

Abstract Senile osteoporosis is mainly caused by osteoblasts attenuation, which results in reduced bone mass and disrupted remodeling. Numerous studies have focused on the regulatory role of m6A modification osteoporosis; however, most investigated differentiation marrow mesenchymal stem cells (BMSCs), while direct mechanism remains unknown. This study revealed that progression senile closely related to downregulation methyltransferase-like 3 (METTL3). Overexpression METTL3 inhibits osteoblast aging. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) upregulates stability Hspa1a mRNA, thereby inhibiting Moreover, demonstrated enhances mRNA via regulate Notably, YTH N6-methyladenosine binding protein 2 (YTHDF2) participates stabilizing METTL3-mediated process, rather than well-known degradation function. Mechanistically, increases a YTHDF2-dependent manner inhibit Our confirmed significant aging suggested could be potential therapeutic target for osteoporosis.

Язык: Английский

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Gut microbially produced tryptophan metabolite melatonin ameliorates osteoporosis via modulating SCFA and TMAO metabolism

Journal of Pineal Research, Год журнала: 2024, Номер 76(3)

Опубликована: Апрель 1, 2024

Abstract Osteoporosis (OP) is a severe global health issue that has significant implications for productivity and human lifespan. Gut microbiota dysbiosis been demonstrated to be closely associated with OP progression. Melatonin (MLT) an important endogenous hormone modulates bone metabolism, maintains homeostasis, improves Multiple studies indicated MLT participates in the regulation of intestinal gut barrier function. However, promising effects microbiota‐derived remain unclear. Here, we found resulted tryptophan disorder decreased production MLT, while administration could mitigate OP‐related clinical symptoms reverse dysbiosis, including diversity microbiota, relative abundance many probiotics such as Allobaculum Parasutterella , metabolic function flora amino acid nucleotide energy metabolism. Notably, significantly increased short‐chain fatty acids trimethylamine N‐oxide‐related metabolites. Importantly, modulate dynamic balance M1/M2 macrophages, reduce serum levels pro‐inflammatory cytokines, restore gut‐barrier Taken together, our results highlighted roles microbially derived progression via “gut‐bone” axis SCFA which may provide novel insight into development drug treating OP.

Язык: Английский

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Gold-nanosphere mitigates osteoporosis through regulating TMAO metabolism in a gut microbiota-dependent manner

Journal of Nanobiotechnology, Год журнала: 2023, Номер 21(1)

Опубликована: Апрель 11, 2023

Osteoporosis (OP) is a metabolic bone disease characterized by decreased mass and increased fragility. The imbalance of homeostasis modulated osteoclasts osteoblasts the most crucial pathological change in osteoporosis. As novel treatment strategy, nanomedicine has been applied drug delivery targeted therapy due to its high efficiency, precision, fewer side effects. Gold nanospheres (GNS), as common kind gold nanoparticles (GNPs), possess significant antimicrobial anti-inflammatory activity, which have for eye diseases rheumatoid arthritis. However, effect GNS on osteoporosis remains elusive. In this study, we found that significantly prevented ovariectomy (OVX)-induced gut microbiota-dependent manner. 16S rDNA gene sequencing demonstrated markedly altered microbial diversity flora composition. addition, reduced abundance TMAO-related metabolites OVX mice. Low TMAO levels might alleviate loss phenomenon reducing inflammation response. Therefore, investigated alteration cytokine profiles inhibited release pro-osteoclastogenic or proinflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin (IL)-6, granulocyte colony-stimulating (G-CSF) serum. conclusion, suppressed estrogen deficiency-induced regulating destroyed microbiota so reduce relevant metabolism restrain cytokines. These results protective effects modulator offered insights into regulation "gut-bone" axis.

Язык: Английский

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METTL14 promotes fibroblast-like synoviocytes activation via the LASP1/SRC/AKT axis in rheumatoid arthritis

AJP Cell Physiology, Год журнала: 2023, Номер 324(5), С. C1089 - C1100

Опубликована: Март 7, 2023

The objective of this study is to explore the specific roles a crucial N6-methyladenosine (m6A) methyltransferase, methyltransferase-like 14 (METTL14), in fibroblast-like synoviocytes (FLSs) activation rheumatoid arthritis (RA). RA rat model was induced by administering intraperitoneally collagen antibody alcohol. Primary were isolated from joint synovium tissues rats. shRNA transfection tools used downregulate METTL14 expression vivo and vitro. injury shown hematoxylin eosin (HE) staining. cell apoptosis FLSs determined flow cytometry. levels IL-6, IL-18, C-X-C motif chemokine ligand (CXCL)10 serum culture supernatants measured ELISA kits. expressions LIM SH3 domain protein 1 (LASP1), p-SRC/SRC, p-AKT/AKT Western blots. greatly rats compared with normal control Compared sh-NC-treated FLSs, knockdown significantly increased apoptosis, inhibited migration invasion, suppressed production CXCL10 TNF-α. silencing suppresses LASP1 Src/AKT axis TNF-α FLSs. improves mRNA stability through m6A modification. In contrast, these reversed overexpression. Moreover, clearly alleviates inflammation model. These results suggested that promotes related inflammatory response via LASP1/SRC/AKT signaling pathway identified as potential target for treating RA.

Язык: Английский

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Recent advances of m6A methylation in skeletal system disease

Journal of Translational Medicine, Год журнала: 2024, Номер 22(1)

Опубликована: Фев. 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

Язык: Английский

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Tricarboxylic Acid Cycle Regulation of Metabolic Program, Redox System, and Epigenetic Remodeling for Bone Health and Disease

Antioxidants, Год журнала: 2024, Номер 13(4), С. 470 - 470

Опубликована: Апрель 17, 2024

Imbalanced osteogenic cell-mediated bone gain and osteoclastic remodeling accelerates the development of osteoporosis, which is leading risk factor disability in elderly. Harmonizing metabolic actions bone-making cells resorbing to mineralized matrix network required maintain mass homeostasis. The tricarboxylic acid (TCA) cycle mitochondria a crucial process for cellular energy production redox canonical TCA enzymes intermediates are indispensable oxidative phosphorylation adenosine triphosphate (ATP) biosynthesis differentiation osteoclast formation. Knockout mouse models identify these enzymes’ roles microarchitecture. In noncanonical processes, metabolites as co-factor or substrate involve epigenetic modification, including histone acetyltransferases, DNA demethylases, RNA m6A affect genomic stability chromatin accessibility cell metabolism formation resorption. genetic manipulation regulators intermediate supplementation compromises age, estrogen deficiency, inflammation-induced loss microstructure deterioration. This review sheds light on functions terms integrity highlights crosstalk pathways skeletal tissue treatment options delaying osteoporosis.

Язык: Английский

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YBX1 alleviates ferroptosis in osteoporosis via the ATF4/FSP1 axis in an m5C manner

Journal of Orthopaedic Surgery and Research, Год журнала: 2025, Номер 19(1)

Опубликована: Янв. 4, 2025

Interactions between RNA-binding proteins and RNA regulate transcription during osteoporosis. Ferroptosis, a programmed cell death caused by iron metabolism, plays vital role in However, the mechanisms which are involved ferroptosis osteoporosis remain unclear. We established an vitro model of induced D-galactose (D-gal) MC3T3-E1 cells. Ferroptosis suppressor protein 1 (FSP1), activating factor 4 (ATF4), Y-box binding (YBX1) knockdown cells were generated, their effects on verified measuring lipid reactive oxygen species levels cellular Fe2+. Chromatin immunoprecipitation luciferase assays performed to confirm ATF4 FSP1 promoter. pulldown experiments used determine YBX1 mRNA test effect stability 5-methylcytosine (m5C)-dependent manner. or led D-gal-induced increase Fe2+ cells, was alleviated overexpression. inhibits In addition, increased through m5C modification inhibited via ATF4/FSP1 axis. Our results showed that could alleviate axis m5C-dependent manner osteoblasts, suggesting may be new target for treatment.

Язык: Английский

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Epigenetic Mechanisms in Osteoporosis: Exploring the Power of m⁶A RNA Modification

Journal of Cellular and Molecular Medicine, Год журнала: 2025, Номер 29(1)

Опубликована: Янв. 1, 2025

ABSTRACT Osteoporosis, recognised as a metabolic disorder, has emerged significant burden on global health. Although available treatments have made considerable advancements, they remain inadequately addressed. In recent years, the role of epigenetic mechanisms in skeletal disorders garnered substantial attention, particularly concerning m 6 A RNA modification. is most prevalent dynamic and reversible modification eukaryotes, mediating various processes mRNAs, including splicing, structural conversion, translation, translocation degradation serves crucial component Research increasingly validated that plays vital proliferation, differentiation, migration, invasion,and repair bone marrow mesenchymal stem cells (BMSCs), osteoblasts osteoclasts, all which impact whole process osteoporosis pathogenesis. Continuous efforts been to target regulators natural products derived from traditional medicine, exhibit multiple biological activities such anti‐inflammatory anticancer effects, valuable resources for drug discovery. This paper elaborates methylation its regulatory osteoporosis, emphasising implications diagnosis treatment, thereby providing theoretical references.

Язык: Английский

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Increased Alleviation of Bone Destruction in Individuals with Rheumatoid Arthritis via the Coinhibition of the METTL3 and YTHDF1 Axis by the Combination of Triptolide and Medicarpin

Engineering, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

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YTHDC1 Modulates the Osteogenic Capacity of hPDLSCs via Wnt/β‐Catenin Signalling Pathway for the Treatment of Bone Defects in Osteoporosis Rats

Cell Proliferation, Год журнала: 2025, Номер unknown

Опубликована: Март 17, 2025

ABSTRACT Human periodontal ligament stem cells (hPDLSCs) have emerged as promising candidates for the treatment of osteoporotic bone defects. Previous studies indicated that m 6 A plays a crucial role in regulating osteogenic differentiation hPDLSCs. However, research on relationship between YTHDC1, reading protein, and hPDLSCs remains unexplored. This study aimed to investigate biological roles YTHDC1 explore underlying mechanisms. Dot blot analysis revealed progressive increase methylation during differentiation, accompanied by significant upregulation expression, evidenced qPCR Western blot. Functional assays utilising siRNA‐mediated knockdown lentiviral‐mediated overexpression demonstrated positively regulated potential Mechanistically, mRNA‐seq implicated Wnt/β‐catenin signalling pathway, which was further validated through rescue experiments with Wnt inhibitor DKK1. Notably, vivo showed overexpressing exhibited enhanced formation capacity rats. In conclusion, our findings suggested modulated highlighting its therapeutic treating defects conditions.

Язык: Английский

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