Role of m6A in osteoporosis, arthritis and osteosarcoma (Review)

Hu, Yibo; Zhao, Xiaohui

doi:10.3892/etm.2021.10358

Cited by 22 publications

(14 citation statements)

References 196 publications

(243 reference statements)

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“…52,54 METTL3 is the key m 6 A writer that has been implicated in the pathogenesis and development of bone-related diseases including osteoporosis, arthritis and osteosarcoma. 55 However, controversy exists regarding the expression of METTL3 and occurrence and development of osteoporosis. For instance, one study reported that disruption of METTL3 in mice destroyed bone formation, impaired osteogenic differentiation and improved marrow adiposity whereas overexpression of METTL3 in BMMSCs protected mice against osteoporosis caused by estrogen deficiency.…”

Section: Relative Protein Expressionmentioning

confidence: 99%

Activation of osteoblast ferroptosis via the METTL3/ASK1‐p38 signaling pathway in high glucose and high fat (HGHF)‐induced diabetic bone loss

Lin

Shen

et al. 2022

The FASEB Journal

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Diabetes mellitus (DM) and osteoporosis are two common diseases that may develop as a cause-and-effect relationship since the incidence of osteoporotic fractures is significantly increased in DM patients. However, the pathophysiology of diabetic osteoporosis is yet to be clearly understood. Iron overload has been reported to lead to bone loss and closely related to osteoporosis. In this study, we hypothesized that high glucose and high fat (HGHF) may induce osteoblastic ferroptosis for the pathogenesis of diabetic osteoporosis and explored the possible molecular mechanisms behind. Using the diabetic rat model established by HGHF feeding with a subsequent intraperitoneal injection of a single low dose of streptozocin, we found that the serum ferritin level (a biomarker for body iron store) was significantly elevated in HGHF-fed rats and the expression of SLC7A11 and GPX4 (inhibitory marker proteins for ferroptosis) was markedly attenuated in the bone tissue of the rats with diabetic bone loss as compared to the normal rats. In an osteoblast cell model, treatment of pre-osteoblastic MC3T3-E1 cells with high glucose and palmitic acid (HGPA) not only suppressed osteoblast differentiation and mineralization but also triggered ferroptosis-related osteoblastic cell death. m 6 A-seq revealed that m 6 A methylation on ASK1 was 80.9-fold higher in HGPA-treated cells. The expression of p-ASK1 and p-p38 was also significantly elevated in the HGPA-treated cells. Knockout of METTL3 (methyltransferaselike 3), one of the major m 6 A methyltransferases, in MC3T3-E1 cells not only abrogated HGPA-induced activation of ASK1-p38 signaling pathway but also attenuated the level of ferroptosis. Therefore, HGHF-induced ferroptosis in osteoblasts may be the main cause of osteoporosis in DM via activation of METTL3/ How to cite this article: Lin Y, Shen X, Ke Y, et al. Activation of osteoblast ferroptosis via the METTL3/ASK1-p38 signaling pathway in high glucose and high fat (HGHF)-induced diabetic bone loss.

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Section: Relative Protein Expressionmentioning

confidence: 99%

Activation of osteoblast ferroptosis via the METTL3/ASK1‐p38 signaling pathway in high glucose and high fat (HGHF)‐induced diabetic bone loss

Lin

Shen

et al. 2022

The FASEB Journal

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“…m6A modification is closely related to the occurrence and development of cancer and participates in cell differentiation, proliferation, migration, immunity, and drug resistance. Deregulation of m6A regulators in OS is inevitable [ 11 , 13 , 30 , 31 ]. Miao et al reported that METTL3 contributes to proliferation, migration, and invasion of OS cells and activates the Wnt/β-catenin signaling pathway by regulating m6A modification of LEF1 mRNAs [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

Fat mass and obesity associated (FTO)-mediated N6-methyladenosine modification of Krüppel-like factor 3 (KLF3) promotes osteosarcoma progression

Shan

Duan

et al. 2022

Bioengineered

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ARSTRACT N6-methyladenosine (m6A) methylation is the most common and abundant methylation modification of eukaryotic mRNAs, which is involved in tumor initiation and progression. The study aims to explore the potential role and the regulatory mechanism of fat mass and obesity associated (FTO) in osteosarcoma (OS) progression. In this study, we detected the expressions of Krüppel-like factor 3 (KLF3) in OS cells and tissues and found that the mRNA and protein levels of KLF3 were increased in OS cells and tissues and significantly related to tumor size, metastasis, and TNM stage and poor prognosis of OS patients. FTO promoted the proliferation and invasion and suppressed apoptosis of OS cells through cell experiments in vitro. Further mechanism dissection revealed that FTO and YTHDF2 enforced the decay of KLF3 mRNA and decreased its expression. FTO-mediated mRNA demethylation inhibited KLF3 expression in the YTHDF2-dependent manner. Moreover, KLF3 overexpression abrogated FTO-induced oncogenic effects on the proliferation and invasion of OS cells. Overall, our findings showed that FTO-mediated m6A modification of KLF3 promoted OS progression, which may provide a therapeutic target for OS.

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“…Bone development and remodeling require precise regulation of gene expression through epigenetics, including RNA modifications. M6A plays an important role in the development and metabolism of bone [ 13 , 14 ]. It affects various bone diseases, such as OP, bone tumors, and arthritis [ 13 , 15 ].…”

Section: Discussionmentioning

confidence: 99%

“…M6A plays an important role in the development and metabolism of bone [ 13 , 14 ]. It affects various bone diseases, such as OP, bone tumors, and arthritis [ 13 , 15 ]. BMSCs maintain a balance between osteogenic and adipogenic differentiation to maintain bone health.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of METTL14 improves postmenopausal osteoporosis via IGF2BP1 dependent posttranscriptional silencing of SMAD1

Huang

Wang

2022

Cell Death Dis

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Osteoporosis (OP) tends to occur in postmenopausal women, making them prone to fractures. N6-methyladenosine (m6A) methylation plays a crucial role in OP. Herein, we aimed to explore the effects of METTL14 on osteogenesis and the underlying mechanism. Osteogenic differentiation was assessed through osteoblast markers expression, cell proliferation, ALP activity, and mineralization, which were detected by qRT-PCR, CCK-8, EdU assay, ALP staining assay, and ARS staining assay, respectively. Osteoporosis was evaluated in OVX mice using qRT-PCR, microcomputed tomography, and H&E staining assay. The levels of METTL14 and SMAD1 were measured using qRT-PCR and western blot, and their interaction was assessed using RIP and luciferase reporter assay. M6A methylation was analyzed using the Me-RIP assay. The results indicated that m6A, METTL14, and SMAD1 levels were downregulated in patients with OP and OVX mice, and upregulated in osteogenic BMSCs. Knockdown of METTL14 suppressed osteogenesis of BMSCs and reduced bone mass of OVX mice. Moreover, silencing of METTL14 positively related to SMAD1 and inhibited m6A modification of SMAD1 by suppressing its stability. IGF2BP1 was identified as the methylation reader, and which knockdown reversed the upregulation induced by SMAD1. Overexpression of SMAD1 reversed the suppression of osteogenic differentiation induced by METTL14 knockdown. In conclusion, interference with METTL14 inhibited osteogenic differentiation of BSMCs by m6A modification of SMAD1 in an IGFBP1 manner, suggesting that METTL14 might be a novel approach for improving osteoporosis.

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Role of m6A in osteoporosis, arthritis and osteosarcoma (Review)

Cited by 22 publications

References 196 publications

Activation of osteoblast ferroptosis via the METTL3/ASK1‐p38 signaling pathway in high glucose and high fat (HGHF)‐induced diabetic bone loss

Activation of osteoblast ferroptosis via the METTL3/ASK1‐p38 signaling pathway in high glucose and high fat (HGHF)‐induced diabetic bone loss

Fat mass and obesity associated (FTO)-mediated N6-methyladenosine modification of Krüppel-like factor 3 (KLF3) promotes osteosarcoma progression

Downregulation of METTL14 improves postmenopausal osteoporosis via IGF2BP1 dependent posttranscriptional silencing of SMAD1

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