Mettl3 Regulates Osteogenic Differentiation and Alternative Splicing of Vegfa in Bone Marrow Mesenchymal Stem Cells

Tian, Cheng; Huang, Yao; Li, Qimeng; Feng, Zhihui; Xu, Qiong

doi:10.3390/ijms20030551

Cited by 110 publications

(110 citation statements)

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“…It was demonstrated that the deletion of METTL3 significantly promoted the pBMSCs adipogenesis process and janus kinase 1 (JAK1) protein expression via an m 6 A-dependent way (55) (Figure 2). Similarly, in Tian's study, it was shown that METTL3 was highly expressed in osteogenically differentiated BMSCs (54). METTL3 knockdown limited the expression of vascular endothelial growth factor (VEGF) and its bone formation-related splice variants (Vegfa-164 and Vegfa188) in osteoblast-induced BMSCs, which was implicated in the maturation of osteoblasts, ossification and bone turnover.…”

Section: A Modification Regulates Bone Developmentmentioning

confidence: 85%

“…It is the most prevalent and internal modification that is tightly related to fundamental biological processes (Figure 1). M 6 A has recently been reported to play a part in pluripotency differentiation and development of the cell lineage (29,30,32,33), including osteogenic differentiation of bone marrow stem cells (BMSCs) (51,53,54). The human skeleton is a metabolically active tissue that undergoes continuous turnover and remodeling throughout life (48).…”

Section: A Modification Regulates Bone Developmentmentioning

confidence: 99%

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Regulatory Role of RNA N6-Methyladenosine Modification in Bone Biology and Osteoporosis

et al. 2020

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Osteoporosis is a metabolic skeletal disorder in which bone mass is depleted and bone structure is destroyed to the degree that bone becomes fragile and prone to fractures. Emerging evidence suggests that N 6-methyladenosine (m 6 A) modification, a novel epitranscriptomic marker, has a significant role in bone development and metabolism. M 6 A modification not only participates in bone development, but also plays important roles as writers and erasers in the osteoporosis. M 6 A methyltransferase METTL3 and demethyltransferase FTO involves in the delicate process between adipogenesis differentiation and osteogenic differentiation, which is important for the pathological development of osteoporosis. Conditional knockdown of the METTL3 in bone marrow stem cells (BMSCs) could suppress PI3K-Akt signaling, limit the expression of bone formation-related genes (such as Runx2 and Osterix), restrain the expression of vascular endothelial growth factor (VEGF) and down-regulate the decreased translation efficiency of parathyroid hormone receptor-1 mRNA. Meanwhile, knockdown of the METTL3 significantly promoted the adipogenesis process and janus kinase 1 (JAK1) protein expression via an m 6 A-dependent way. Specifically, there was a negative correlation between METTL3 expression and porcine BMSCs adipogenesis. The evidence above suggested that the relationship between METTL3 expression and adipogenesis was inverse, and osteogenesis was positive, respectively. Similarly, FTO regulated for BMSCs fate determination during osteoporosis through the GDF11-FTO-PPARγ axis, prompting the shift of MSC lineage commitment to adipocyte and inhibiting bone formation during osteoporosis. In this systematic review, we summarize the most up-to-date evidence of m 6 A RNA modification in osteoporosis and highlight the potential role of m 6 A in prevention, treatment, and management of osteoporosis.

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Section: A Modification Regulates Bone Developmentmentioning

confidence: 85%

Section: A Modification Regulates Bone Developmentmentioning

confidence: 99%

Regulatory Role of RNA N6-Methyladenosine Modification in Bone Biology and Osteoporosis

et al. 2020

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“…A recent study indicated that silencing METTL3 markedly promoted the porcine BMSC adipogenesis process by targeting the JAK1/STAT5/C/EBPβ pathway via an m 6 A-YTHDF2-dependent regulatory pattern [23]. METTL3 depletion suppressed the osteogenic differentiation potential of BMSCs and decreased the expression of Vegfa splice variants [28]. In the present study, to investigate the effect of METTL3 on bone-forming function in an inflammatory environment, the osteogenesis process was evaluated in siMETTL3 treated osteoblasts with or without LPS.…”

Section: Discussionmentioning

confidence: 99%

“…A recent in vivo study demonstrated that the reduced m 6 A modifications in bone marrow mesenchymal stem cells (BMSCs) disrupt the osteogenic and adipogenic responses induced by parathyroid hormone, resulting in severe bone loss and excessive adipose accumulation [27]. Our previous study also showed that METTL3 loss inhibited the osteogenic differentiation potential of BMSCs [28]. Nevertheless, little is known about the role of METTL3 in osteoblast function during the inflammatory process.…”

Section: Introductionmentioning

confidence: 98%

METTL3 Regulates Osteoblast Differentiation and Inflammatory Response via Smad Signaling and MAPK Signaling

Zhang

et al. 2019

IJMS

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113

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Osteoblasts are crucial bone-building cells that maintain bone homeostasis, whereas inflammatory stimuli can inhibit osteogenesis and activate inflammatory response. N6-methyladenosine (m6A) is the most abundant mRNA modification in eukaryotes and plays important roles in multiple biological processes. However, whether m6A modification affects osteoblast differentiation and inflammatory response remains unknown. To address this issue, we investigated the expression of the N6-adenosine methyltransferase METTL3 and found that it was upregulated during osteoblast differentiation and downregulated after LPS stimulation. We then knocked down METTL3 and observed decreased levels of osteogenic markers, ALP activity, and mineralized nodules, as well as Smad1/5/9 phosphorylation, in LPS-induced inflammation. METTL3 knockdown promoted the mRNA expression and stability of negative regulators of Smad signaling, Smad7 and Smurf1, the same regulatory pattern identified when the m6A-binding protein YTHDF2 was silenced. Moreover, METTL3 depletion enhanced proinflammatory cytokine expression and increased the phosphorylation of ERK, p38, JNK, and p65 in MAPK and NF-κB signaling pathways. The increase in cytokine expression was inhibited after MAPK signaling inhibitor treatment. All data suggest that METTL3 knockdown inhibits osteoblast differentiation and Smad-dependent signaling by stabilizing Smad7 and Smurf1 mRNA transcripts via YTHDF2 involvement and activates the inflammatory response by regulating MAPK signaling in LPS-induced inflammation.

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“…As an RNA epigenetic modification, m 6 A has been indicated to be essential in regulating osteogenic differentiation. The results of our previous study demonstrated that attenuated m 6 A levels upon Mettl3 deficiency inhibits the osteogenic differentiation potential of bone mesenchymal stem cells (BMSCs) [31]. Another in vivo study using genetic murine models also shows that the conditional depletion of Mettl3 in BMSCs creates an osteopenia phenotype due to incompetent osteogenic potential [32].…”

Section: Introductionmentioning

confidence: 93%

METTL3 Modulates Osteoclast Differentiation and Function by Controlling RNA Stability and Nuclear Export

Cai

Meng

et al. 2020

IJMS

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Osteoclast differentiation and function are crucial for maintaining bone homeostasis and preserving skeletal integrity. N6-methyladenosine (m6A) is an abundant mRNA modification that has recently been shown to be important in regulating cell lineage differentiation. Nevertheless, the effect of m6A on osteoclast differentiation remains unknown. In the present study, we observed that the m6A level and methyltransferase METTL3 expression increased during osteoclast differentiation. Mettl3 knockdown resulted in an increased size but a decreased bone-resorbing ability of osteoclasts. The expression of osteoclast-specific genes (Nfatc1, c-Fos, Ctsk, Acp5 and Dcstamp) was inhibited by Mettl3 depletion, while the expression of the cellular fusion-specific gene Atp6v0d2 was upregulated. Mechanistically, Mettl3 knockdown elevated the mRNA stability of Atp6v0d2 and the same result was obtained when the m6A-binding protein YTHDF2 was silenced. Moreover, the phosphorylation levels of key molecules in the MAPK, NF-κB and PI3K-AKT signaling pathways were reduced upon Mettl3 deficiency. Depletion of Mettl3 maintained the retention of Traf6 mRNA in the nucleus and reduced the protein levels of TRAF6. Taken together, our data suggest that METTL3 regulates osteoclast differentiation and function through different mechanisms involving Atp6v0d2 mRNA degradation mediated by YTHDF2 and Traf6 mRNA nuclear export. These findings elucidate the molecular basis of RNA epigenetic regulation in osteoclast development.

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Mettl3 Regulates Osteogenic Differentiation and Alternative Splicing of Vegfa in Bone Marrow Mesenchymal Stem Cells

Cited by 110 publications

References 103 publications

Regulatory Role of RNA N6-Methyladenosine Modification in Bone Biology and Osteoporosis

Regulatory Role of RNA N6-Methyladenosine Modification in Bone Biology and Osteoporosis

METTL3 Regulates Osteoblast Differentiation and Inflammatory Response via Smad Signaling and MAPK Signaling

METTL3 Modulates Osteoclast Differentiation and Function by Controlling RNA Stability and Nuclear Export

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