RNA N6-methyladenosine demethylase FTO promotes osteoporosis through demethylating Runx2 mRNA and inhibiting osteogenic differentiation

Wang, Jing; Fu, Qiang; Yang, Jian; Liu, Jinlong; Hou, Shuming; Huang, Xing; Cao, Jiantao; Liu, Tielong; Wang, Kunzheng

doi:10.18632/aging.203377

Cited by 36 publications

(39 citation statements)

References 21 publications

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“…Xie et al revealed that TNF-α induced m6A modification in ELMO1 3′UTR triggers directional migration of mesenchymal stem cell in ankylosing spondylitis patients [ 30 ]. Wang et al elucidated a new pathogenesis of osteoporosis, that is, FTO mediates Runx2 mRNA demethylation to inhibit the osteogenic differentiation of BMSCs [ 31 ]. However, the roles of m6A modification and the underlying regulatory mechanisms in SONFH remain unclear.…”

Section: Introductionmentioning

confidence: 99%

METTL14 benefits the mesenchymal stem cells in patients with steroid-associated osteonecrosis of the femoral head by regulating the m6A level of PTPN6

Cheng

Zhang

Zheng

et al. 2021

Aging

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Imbalanced osteogenic/adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is considered the core pathological characteristic of steroid-associated osteonecrosis of the femoral head (SONFH). N6-Methyladenosine (m6A) is the most common type of RNA modification in eukaryotic cells and participates in various physiological and pathological processes. However, the relationship between m6A modification and SONFH has not been reported. In the present study, we aimed to explore the roles of m6A modifications and methyltransferase METTL14 in SONFH. Our results showed that the m6A levels were down-regulated in femoral head tissues and BMSCs from SONFH patients, and this effect was attributed to the reduction of METTL14. Furthermore, METTL14 overexpression in BMSCs from SONFH patients enhanced cell proliferation and osteogenic differentiation. We further identified PTPN6 as the downstream target of METTL14 by mRNA sequencing. Mechanistically, METTL14 regulated PTPN6 expression by increasing PTPN6 mRNA stability in an m6A-dependent manner. Moreover, PTPN6 knockdown abrogated the beneficial effects of METTL14 overexpression on BMSCs. Additionally, we found that METTL14 activated the Wnt signaling pathway, and this effect was caused by the interaction of PTPN6 and GSK-3β. In conclusion, we elucidated the functional roles of METTL14 and m6A methylation in SONFH BMSCs and identified a novel RNA regulatory mechanism, providing a potential therapeutic target for SONFH.

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Section: Introductionmentioning

confidence: 99%

METTL14 benefits the mesenchymal stem cells in patients with steroid-associated osteonecrosis of the femoral head by regulating the m6A level of PTPN6

Cheng

Zhang

Zheng

et al. 2021

Aging

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“…We found FTO upregulated in OP, whereas YTHDF2 and CBLL1 were downregulated in OP. Previous studies have indicated that FTO inhibits osteogenic differentiation to promote OP ( 26 , 62 ).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of the m6A-related molecular patterns and diagnostic biomarkers in osteoporosis

et al. 2022

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BackgroundN6-methyladenosine (m6A) modification is a critical epigenetic modification in eukaryotes and involves several biological processes and occurrences of diseases. However, the roles and regulatory mechanisms of m6A regulators in osteoporosis (OP) remain unclear. Thus, the purpose of this study is to explore the roles and mechanisms of m6A regulators in OP.MethodsThe mRNA and microRNA (miRNA) expression profiles were respectively obtained from GSE56815, GSE7158, and GSE93883 datasets in Gene Expression Omnibus (GEO). The differential expression of 21 m6A regulators between high-bone mineral density (BMD) and low-BMD women was identified. Then, a consensus clustering of low-BMD women was performed based on differentially expressed (DE)-m6A regulators. The m6A-related differentially expressed genes (DEGs), the differentially expressed miRNAs (DE-miRNAs), and biological functions were investigated. Moreover, a weighted gene co-expression network analysis (WGCNA) was constructed to identify the OP-related hub modules, hub genes, and the functional pathways. Then, an m6A regulator–target–pathway network and the competing endogenous RNA (ceRNA) network in key modules were constructed. A least absolute shrinkage and selection operation (LASSO) Cox regression model and a Support Vector Machine-Recursive Feature Elimination (SVM-RFE) model were constructed to identify the candidate genes for OP prediction. The receiver operator characteristic (ROC) curves were used to validate the performances of predictive models and candidate genes.ResultsA total of 10,520 DEGs, 13 DE-m6A regulators, and 506 DE-miRNAs between high-BMD and low-BMD women were identified. Two m6A-related subclusters with 13 DE-m6A regulators were classified for OP. There were 5,260 m6A-related DEGs identified between two m6A-related subclusters, the PI3K-Akt, MAPK, and immune-related pathways, and bone metabolism was mainly enriched in cluster 2. Cell cycle-related pathways, RNA methylation, and cell death-related pathways were significantly involved in cluster 1. Five modules were identified as key modules based on WGCNA, and an m6A regulator–target gene–pathway network and the ceRNA network were constructed in module brown. Moreover, three m6A regulators (FTO, YTHDF2, and CBLL1) were selected as the candidate genes for OP.ConclusionM6A regulators play an important role in the occurrences and diagnosis of OP.

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“…Osteoporosis is a bone aging disease. m 6 A modification have been reported to be involved in regulating the proliferation, differentiation, and apoptosis of bone-related cells including bone marrow mesenchymal stem cells, osteoblasts, and osteoclasts by multiple studies ( Huang et al, 2021 ) ( Wang et al, 2021b ; Chen et al, 2022 ) ( Wu et al, 2020 ). In addition, IGF2BP2 highly expressed in Alzheimer’s patients by bioinformatic analysis using multiple RNA-seq datasets of Alzheimer’s brain tissues ( Deng et al, 2021 ).…”

Section: M 6 a Methylation Modification In Female ...mentioning

confidence: 99%

The Role of m6A on Female Reproduction and Fertility: From Gonad Development to Ovarian Aging

Sun

et al. 2022

Front. Cell Dev. Biol.

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The growth and maturation of oocyte is accompanied by the accumulation of abundant RNAs and posttranscriptional regulation. N6-methyladenosine (m6A) is the most prevalent epigenetic modification in mRNA, and precisely regulates the RNA metabolism as well as gene expression in diverse physiological processes. Recent studies showed that m6A modification and regulators were essential for the process of ovarian development and its aberrant manifestation could result in ovarian aging. Moreover, the specific deficiency of m6A regulators caused oocyte maturation disorder and female infertility with defective meiotic initiation, subsequently the oocyte failed to undergo germinal vesicle breakdown and consequently lost the ability to resume meiosis by disrupting spindle organization as well as chromosome alignment. Accumulating evidence showed that dysregulated m6A modification contributed to ovarian diseases including polycystic ovarian syndrome (PCOS), primary ovarian insufficiency (POI), ovarian aging and other ovarian function disorders. However, the complex and subtle mechanism of m6A modification involved in female reproduction and fertility is still unknown. In this review, we have summarized the current findings of the RNA m6A modification and its regulators in ovarian life cycle and female ovarian diseases. And we also discussed the role and potential clinical application of the RNA m6A modification in promoting oocyte maturation and delaying the reproduction aging.

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RNA N6-methyladenosine demethylase FTO promotes osteoporosis through demethylating Runx2 mRNA and inhibiting osteogenic differentiation

Cited by 36 publications

References 21 publications

METTL14 benefits the mesenchymal stem cells in patients with steroid-associated osteonecrosis of the femoral head by regulating the m6A level of PTPN6

METTL14 benefits the mesenchymal stem cells in patients with steroid-associated osteonecrosis of the femoral head by regulating the m6A level of PTPN6

Comprehensive analysis of the m6A-related molecular patterns and diagnostic biomarkers in osteoporosis

The Role of m6A on Female Reproduction and Fertility: From Gonad Development to Ovarian Aging

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