Home Journals Articles Updates About
CN
image
收藏切换
N6-Methyladenosine in Cell-Fate Determination of BMSCs: From Mechanism to Applications
收藏切换
PDF
Qingyu Zhang1, Junyou Li2, Cheng Wang3, Zhizhuo Li4, Pan Luo5, Fuqiang Gao6, *, Wei Sun6, 7, *
Research. Vol 7 Article ID 0340
Less
收藏切换
Research. Vol 7 Article ID 0340
• Review Article •
N6-Methyladenosine in Cell-Fate Determination of BMSCs: From Mechanism to Applications
Full
Qingyu Zhang1, Junyou Li2, Cheng Wang3, Zhizhuo Li4, Pan Luo5, Fuqiang Gao6, *, Wei Sun6, 7, *
Affiliations
  • 1Department of Orthopedics, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan 250021, China.
  • 2School of Mechanical Engineering, Sungkyunkwan University, Suwon 16419, South Korea.
  • 3Department of Orthopaedic Surgery, Peking University Third Hospital, Peking University, Beijing 100191, China.
  • 4State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China.
  • 5Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an 710054, China.
  • 6 Department of Orthopedics, China-Japan Friendship Hospital, Beijing 100029, China.
  • 7Department of Orthopaedic Surgery of the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Published: 2024-04-25 doi: 10.34133/research.0340
Outline
收藏切换

The methylation of adenosine base at the nitrogen-6 position is referred to as “N6-methyladenosine (m6A)” and is one of the most prevalent epigenetic modifications in eukaryotic mRNA and noncoding RNA (ncRNA). Various m6A complex components known as “writers,” “erasers,” and “readers” are involved in the function of m6A. Numerous studies have demonstrated that m6A plays a crucial role in facilitating communication between different cell types, hence influencing the progression of diverse physiological and pathological phenomena. In recent years, a multitude of functions and molecular pathways linked to m6A have been identified in the osteogenic, adipogenic, and chondrogenic differentiation of bone mesenchymal stem cells (BMSCs). Nevertheless, a comprehensive summary of these findings has yet to be provided. In this review, we primarily examined the m6A alteration of transcripts associated with transcription factors (TFs), as well as other crucial genes and pathways that are involved in the differentiation of BMSCs. Meanwhile, the mutual interactive network between m6A modification, miRNAs, and lncRNAs was intensively elucidated. In the last section, given the beneficial effect of m6A modification in osteogenesis and chondrogenesis of BMSCs, we expounded upon the potential utility of m6A-related therapeutic interventions in the identification and management of human musculoskeletal disorders manifesting bone and cartilage destruction, such as osteoporosis, osteomyelitis, osteoarthritis, and bone defect.

Qingyu Zhang, Junyou Li, Cheng Wang, Zhizhuo Li, Pan Luo, Fuqiang Gao, Wei Sun. N6-Methyladenosine in Cell-Fate Determination of BMSCs: From Mechanism to Applications[J]. Research, 2024 , 7 (4) : 0340 . DOI: 10.34133/research.0340
Full Text
Less
Introduction
Less
Bone has a self-repair ability so that it can renew itself when the nature and extent of the defect are not large, severe, and chronic [1–3]. The reparative process of bone is initiated by bone mesenchymal stem cells (BMSCs) residing in the bone marrow, which are multipotent stem cells with the ability to differentiate into various cell types, including osteoblasts, adipocytes, chondrocytes, and fibroblasts [1,2,4]. Data analysis revealed two distinct phases of the BMSC differentiation process, namely, lineage commitment (from MSCs to lineage-specific progenitors) and maturation (from progenitors to specific cell types) [2]. The dysregulation of adipose-osteogenic balance could result in the formation of excessive fat and compromised bone structure, contributing to the pathogenesis of multiple musculoskeletal conditions [5,6]. The differentiation of BMSCs is regulated by the activation of specific intracellular transcription factors (TFs), signaling pathways, and noncoding RNAs (ncRNAs; e.g., miRNA, lncRNA, and circRNA) [2,7]. In addition, extracellular elements such as hypoxia and mechanical stimulation are also involved in these vital processes [8].
N6-methyladenosine (m6A) refers to the methylation at the nitrogen-6 position of adenosine, which normally uses S-adenosylmethionine (SAM) as the methyl donor, and ranks as one of the most abundant and conserved epigenetic modifications of messenger RNA (mRNA) and ncRNA in eukaryotes [9,10]. m6A modification is reversible, achieved by proteins known as m6A “writers,” “erasers,” and “readers.” Recent studies have shown that aberrant m6A levels caused by methyltransferase-like 3 (METTL3) are involved in the development and progression of numerous malignancies [e.g., lung cancer and acute myeloid leukemia (AML)], inflammatory diseases, metabolic disorders, and cardiovascular diseases [11–13]. However, the role of m6A modification in bone homeostasis is little known. Increasing evidence has suggested that m6A modification is critical for the differentiation, proliferation, apoptosis, and necrosis of BMSCs, but these findings have not been comprehensively summarized. In this article, we will briefly elaborate on the biological function and clinical value of m6A modification in the differentiation of BMSCs, which may provide possible targets for diagnosing and treating human musculoskeletal diseases such as osteoporosis, osteoarthritis, and osteomyelitis.
Brief Overview of m6A Modification
Less
The m6A methyltransferase complex (MTC; writers) catalyzing the formation of most mRNA m6A consists of a METTL3/METTL14 heterodimer core and other binding partners represented by Wilms tumor 1-associating protein (WTAP) [11,12]. Among this complex, METTL3 is of the most interest from a research standpoint because it is the sole catalytically active subunit of MTC implicated in RNA biogenesis, translation, and degradation, serving as a core protein for m6A modification [11,12,14]. Readers are m6A methyl-binding proteins and mainly include YTHDC1/2, YTHDF1/2/3, and IGF2BP1/2/3 [14,15]. The m6A erasers refer to the demethylases like FTO and ALKBH5 [14,15].
In addition to directly regulating the expression of mRNAs, m6A modification of ncRNAs, especially lncRNAs and miRNAs, has garnered growing interest in recent years, although the number of related studies is much lower (Fig. 1) [14,16]. NcRNAs and m6A may cooperate or compete to jointly regulate target mRNAs [14,16]. Moreover, previous studies have suggested that ncRNAs are the main sites of RNA epigenetic modification [17].
m6A modification regulates the metabolism of mRNA
METTL3 located in the nucleus affects the maturation and transportation of mRNAs [18]. The widespread m6A deposition in pre-mRNA was associated with the mRNA alternative splicing, producing diverse mature mRNA sequences and substantial cellular complexity [19]. Stimulation effects of m6A modification on mRNA transportation from the nucleus to the cytoplasm were also unraveled, which were vital for active translations in eukaryotes [19,20]. In the METTL3-enriched cytoplasm, m6A modification plays an intricate effect on mRNA, mediating mRNA translation efficiency, stability, or degradation depending on the corresponding m6A reader (e.g., YTHDC1/2, YTHDF1/2/3, and IGF2BP1/2/3) [19–22]. Apart from its eminent methyltransferase activity, it has been reported that METTL3 could facilitate the translation initiation of transcripts harboring the m6A-modified 3′-UTR (untranslated region) without the help of m6A reader proteins [15,23].
Mutual regulatory effects between m6A modification and ncRNAs
m6A modification could enhance or decrease the transcript stability of modified lncRNA, alter the subcellular distribution, mediate gene transcription repression, change the lncRNA structures, and affect the interaction with associated proteins [24,25]. The specific methyl-binding proteins that impact the transcript stability of lncRNA are also summarized in Fig. 1. At the same time, mutual regulation exists between lncRNA and METTL3. Shen et al. [26] demonstrated that aspartyl-tRNA synthetase 1 antisense 1 (DARS-AS1), an oncogenic lncRNA, could facilitate the translation of DARS by enlisting METTL3 and METTL14 in cervical cancer.
In mammalian cells, m6A modification of pri-miRNAs facilitates recognition by DGCR8 and enhances miRNA maturation in a global and non-cell type-specific manner [27]. m6A modification could also promote the synthesis of mature miRNAs by accelerating the splicing of pre-miRNAs by Dicer [28]. METTL3 depletion contributes critically to the global reduction of mature miRNAs and concomitant overaccumulation of unprocessed pri-miRNAs, hinting that the m6A mark acts as a key posttranscriptional modification that boosts the initiation of miRNA biogenesis [14]. Simultaneously, certain miRNAs such as miR-186, miR-4429, miR-600, miR-33a, and let-7g can directly target mRNAs of METTL3 and result in translation inhibition [19] [15]. It was also suggested that miR-24-2 might induce METTL3 transcription, although the comprehensive and detailed mechanism was poorly understood [29].
m6A Modification and Osteogenesis of BMSCs
Less
Expression of METTL3 and m6A content in total RNA was robustly up-regulated in BMSCs undergoing osteogenic differentiation [30]. METTL3 loss of function in BMSCs lowers the mRNA level of bone formation-related genes, such as Runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), osteopontin (OPN), and alkaline phosphatase (ALP), hampering osteogenic differentiation and the formation of mineralized nodules [31–33]. In contrast, adenovirus-mediated overexpression of METTL3 produced the opposite effects. However, the expression and influence of FTO and ALKBH5 on osteogenesis of BMSCs are debatable [34–37]. Down-regulation or up-regulation of this m6A demethylase can both disrupt osteogenic differentiation.
m6A modification of TFs during osteogenesis (Table 1 and Fig. 2)
RUNX2 and Osterix are two essential TFs for the osteoblastic differentiation of BMSCs and skeletal morphogenesis, localized within both the nucleus and cytosol [38]. Most signaling pathways (e.g., BMP2/Smad pathway and Wnt/β-catenin pathway) investigated during osteogenesis so far are targeted at RUNX2 [39,40]. RUNX2 is enhanced by core-binding factor β (Cbfβ) and therefore activates OCN, OPN, ALP, and bone sialoprotein [38,41]. Up-regulated RUNX2 in BMSCs elevates their lineage commitment into osteoblasts and impedes their differentiation potential into adipocytes by disturbing the peroxisome proliferator-activated receptor γ (PPARγ) pathway (Fig. S1) [42]. RUNX2 is decreased during maturated osteoblasts, while Osterix is obligatory for the maturation process [43].
RUNX2 is affected by m6A RNA methylation mainly through the dual signaling cascades of osteogenic pathways. On the one hand, METTL3 directly up-regulates m6A methylation of RUNX2, increasing RUNX2 mRNA stability and translation by the recognition of YTHDF1 and IGF2BP1 [33,36]; on the other hand, METTL3 promotes m6A methylation of pre-miR-320 and inhibits the maturation of miR-320 by YTHDF2, which elevates the expression of associated bone fide target genes for miR-320 family including RUNX2 [30]. The BMP2/Smad pathway, which serves as a positive regulator of RUNX2 expression as well as osteoblastic differentiation, is also regulated by m6A modification [39,40]. METTL3 decreased the mRNA maturation and stability of negative regulatory proteins of Smad signaling, Smad and Smurf1 [40]. This inhibitory effect might be reduced by the silence of YTHDF2 [44]. m6A modification of BMP2 transcript accelerates mRNA degradation mediated by YTHDF2 [44]. Nevertheless, the osteogenesis up-regulated piR-36741 could combine with PIWIL4 to create a complex and competitively bind to METTL3 with BMP2 mRNA, decreasing METTL3's m6A activity without altering its level and increasing BMP2 expression [44]. Vascular endothelial growth factor (VEGF) controls the differentiation of BMSCs by regulating RUNX2 and PPARγ as well as through a reciprocal interaction with nuclear envelope proteins lamin A/C [45]. METTL3 could influence the alternative splicing of VEGFA mRNA, increasing the expression level of VEGFA as well as its splice variants, vegfa-164 and vegfa-188 [46].
Osterix/Sp7 is a member of the Sp1 TF family of C2H2-type zinc finger TFs, which functions as a downstream of RUNX2 [47]. Osterix, along with RUNX2 and Dlx5, drives the differentiation of mesenchymal precursor cells into osteoblasts and eventually osteocytes, and inhibits chondrocyte differentiation, maintaining the balance between osteogenesis and chondrogenesis [48]. The m6A methylation of Osterix could also improve the expression of this key osteogenic TF [46]. It is noteworthy that the pre-mRNA of Osterix harbors 56 potential m6A modification sites according to a sequence-based m6A modification site predictor (http://www.cuilab.cn/sramp). By which mechanism m6A modification affects the transcription and expression of Osterix should be further investigated.
m6A modification and affected key genes and signaling pathway during osteogenesis (Table 1 and Fig. 2)
Parathyroid hormone receptor-1 (Pth1r), a vital modulator of lineage commitment in BMSCs and osteoblast precursors, shows a highly concentrated and distinctive m6A peak adjacent to its translation stop codon [49]. Wu et al. [49] found that the translation efficiency of pth1r mRNA was decreased and the parathyroid hormone (PTH)-induced osteogenic effect was hindered after the knockout of METTL3, which confirmed that m6A modification regulates the lineage allocation of MSCs partially by the PTH/Pth1r signaling pathway. In rat BMSCs isolated from osteoporosis models, overexpressing METTL3 restored the osteogenic ability by activating the Wnt/β-catenin signaling pathway and subsequently increased the expression of β-catenin, RUNX2, OPN, P-Gsk-3β, and Lef1 [31]. Mass of genes linked to osteogenic differentiation and bone mineralization were impacted by METTL3 knockdown, with the phosphatidylinositol 3-kinase/AKT (PI3K-Akt) signaling pathway appearing to be among the most abundant pathways [46]. During osteogenesis, an incremental m6A level located in the 3′-UTR of the CAP-Gly domain-containing linker protein 3 (Clip3) mRNA was detected, which leads to accelerated degradation of mRNA and down-regulated Clip3 expression [50].
Although METTL14 only engages in the complex stabilization and RNA recruitment of MTC, it could promote osteogenesis of BMSCs in physiological and pathological conditions by stimulating m6A modification of multiple mRNAs including PTPN6 [51], TCF1 [52], Beclin-1 [53], and SMAD1 [54].
m6A modification and ncRNAs in osteogenesis of BMSCs (Tables 2 and 3 and Fig. 3)
In addition to abovementioned miR-320, further studies uncovered that METTL3 can methylate pri-miR-21 and facilitate the maturation of miR-21 [55], which potentiates the osteogenesis of BMSCs by activating the Smad1/5/8-RUNX2 pathway [56] and lowering the amount of hypoxia-inducible factor-1α (HIF-1α) [57]. WTAP, another critical component of m6A writers, also acts as a promoter of osteogenesis by encouraging mature miR-29b-3p [58] and miR-181a/c [59]. Similar phenomenon was observed between METTL14 and miR-873 [60]. However, some anti-osteogenic miRNAs, such as miR-143-3p [61–66], miR-25-3p [67–71], miR-146a-5p [72–74], miR-30b-5p [75,76], miR-93-5p [77,78], miR-375-3p [79,80], and miR-221/222 [81], were also modulated by m6A modification, which stimulates the miRNA mature. These miRNAs could negatively regulate the osteogenic process by binding mRNAs of pro-osteogenic genes. As an illustration, miR-25-3p specifically targets Smad5 [71] and ITGB3 [70], while miR-221/222 could block RUNX2, Smad3, as well as the insulin-like growth factor 1 (IGF-1)/extracellular signal-regulated kinase (ERK) pathway [82–84].
Some well-recognized lncRNAs enhancing osteogenesis, such as MALAT1 [85–87], NEAT1 [88,89], and H19 [90–102], could also be modulated by m6A modification to increase the stability [103]. Among them, H19 could sponge multiple miRNAs with negative regulatory effects on the Wnt/β-catenin/RUNX2 pathway [90–94], and produce miR-675 to facilitate the production of RUNX2 [104]. MALAT1 could sponge miR-143 [86] and miR-204 [85] to boost the expression of Osterix and Smad4, respectively. Besides, the osteogenic ability of METTL3 on human BMSCs was partially realized through the m6A methylation of LINC00657 and the inhibition of downstream miR-144-3p/BMRPB1 axis [105].
m6A modification in macrophages and osteogenesis of BMSCs
METTL3 in other types of cells in the bone microenvironment could also influence the osteogenesis of BMSCs. Overexpression of METTL3 was identified in the pro-inflammatory type of blood-derived and bone marrow-derived M1 macrophages as compared with non-activated macrophages (M0) [106]. METTL3 overexpression promoted the expression and m6A modification of DUSP14, HDAC5, and Nfam1, which has been reported to slow down the onset of osteoporosis [107].
m6A Modification and Adipogenesis of BMSCs
Less
Numerous investigations have revealed that fat induction factors suppress osteogenesis; rather, osteogenic factors restrain adipogenesis [108]. A negative correlation exists between METTL3 expression and BMSC adipogenesis. METTL3 overexpression reduced lipid droplet formation and dramatically suppressed adipogenic markers PPARγ, C/EBPα (CCAAT/enhancer binding protein α), and FABP4 [109]. FTO is a well-known gene linked to obesity that has the ability to control adipogenesis by m6A demethylation [110].
m6A modification of TFs during adipogenesis (Table 1 and Fig. 2)
PPARγ and C/EBPs (C/EBPα, C/EBPβ, and C/EBPδ) are critical TFs involved in the adipogenic differentiation of BMSCs [111]. After adipogenic differentiation is induced, C/EBPβ and C/EBPδ are swiftly (within 4 h) elevated and subsequently activate C/EBPα and PPARγ [112]. The expression of adipogenic genes that underlie terminally differentiated adipocyte phenotype is coordinated by C/EBPα and PPARγ combined [111,112]. While PPARγ and C/EBPα expression remains high throughout the adipogenic process and the adipocytes' lifetime, C/EBPβ is down-regulated in the later stages of differentiation [111,112].
In particular, METTL3 blocked the adipogenic differentiation of pBMSCs by interfering with the Janus kinase 1 (JAK1)–signal transducer and activator of transcription 5 (STAT5)–C/EBPβ pathway in a way dependent on m6A and YTHDF2 [109]. Deletion of METTL3 significantly decreased mRNA m6A levels of JAK1 to augment its stability [109]. By controlling its phosphorylation, JAK1 may bind to the promoter of C/EBPβ and activate the signal transducer and activator of STAT5, which may trigger a modified adipogenic pathway [109]. Meanwhile, adipogenesis is inhibited by deletion of m6A demethylase FTO via JAK2-STAT3-C/EBPβ signaling [113]. Increased METTL3 in BMSCs reduced PPARγ expression, while METTL3 knockdown had the opposite impact [106]. Conversely, FTO bonded to and demethylated the PPARγ mRNA, which increased the mRNA's expression [114]. PPARγ and C/EBPs all carry potential m6A modification sites, but whether direct m6A modification of these TFs influences the adipogenic differentiation of BMSCs merits further instigation.
ZFP217 is a TF belonging to the Krüppel-type zinc finger protein family and has been proven to take involvement in adipogenesis [115]. The last evidence showed that the adipogenesis induced by ZFP217 knockdown was caused by CCND1, which was mediated by METTL3 and YTHDF2 in an m6A-dependent manner [115]. Runt-related transcription factor 1 translocation partner 1 (RUNX1T1) is another novel adipogenic regulatory factor [116]. By modulating the amounts of m6A around splice sites, FTO regulates the exonic splicing of RUNX1T1, controlling RUNX1T1-S isoform expression and therefore modulating adipogenesis [117].
m6A modification and affected key genes and signaling pathway during adipogenesis (Table 1 and Fig. 2)
Patients with AML have elevated AKT1-mRNA and protein expression due to loss of METTL3, which mediates m6A modification of AKT1-mRNA [106]. This increases the likelihood that MSCs will develop into adipocytes, altering the microenvironments of the bone marrow. The aggregates of adipocytes in bone marrow contribute to chemoresistance in AML. This is in line with former findings that METTL3 speeds up the progression of hematological malignancies [13]. Furthermore, FTO has an impact on the cell cycle. YTHDF2 separates and destabilizes m6A-modified mRNA of two cell cycle regulators, CCNA2 and CDK2 [118]. FTO can demethylate and boost the expression of CCNA2 and CDK2, which in turn shortens the cell cycle and increases adipogenesis of BMSCs.
m6A modification and key ncRNAs in adipogenesis of BMSCs (Table 4 and Fig. 4)
As mentioned before, the m6A modulation accelerates the maturation of pri-miR-221/222 and pri-miR-25-3p. Besides inhibiting osteogenesis-related genes, miR-221/222 could directly boost the adipogenesis processes by targeting Ddit4 [119]. Meanwhile, m6A modification accelerated the mature process of miR-25-3p, which acts as a molecular sponge for KLF4 and C/EBPα and could inhibit adipogenesis [120]. Two miRNAs, namely, miR-149-3p and miR-1322, could inhibit adipogenesis of BMSCs by targeting FTO [121,122].
m6A Modification and Chondrogenesis of BMSCs
Less
During chondrogenesis of BMSCs, the protein and mRNA levels of METTL3 were substantially elevated, which recruits more Nsun4 to form a complex [123]. Similar results were obtained in the synovium-derived mesenchymal stem cells (SMSCs) [124]. In chondrogenic differentiation of SMSCs, the m6A levels were markedly increased and only protein level METTL3 was most obviously raised in comparison with other m6A-related genes [124]. Knockdown of METTL3 suppressed the chondrogenesis of BMSCs and SMSCs [123,124].
m6A modification of TF during chondrogenesis (Table 1 and Fig. 2)
SRY-related high-mobility group box 9 (Sox9) is a critical TF that mediates chondrocyte lineage commitment of BMSCs, benefiting chondrocyte survival by transcriptionally activating the expression of chondrocyte-specific components and regulatory factors, such as collagen type II, type IX, and type XI and aggrecan [125]. The expression of Sox9 was also modulated in the level of epigenetic modification. Nsun4 mediates the m5C alteration in the 3′-UTR of Sox9 mRNA, while METTL3 mediates m6A modification [123]. Together, these modifications co-regulated the translational reprogramming by creating a complex with YTHDF2 and eEF1α-1. In vivo, BMSCs overexpressing METTL3 and Nsun4 can help repair cartilage defects caused by drilling [123]. Knockdown of METTL3 dramatically reduced the expression of SOX9 [124].
m6A modification and key genes and signaling pathway during chondrogenesis (Table 1 and Fig. 2)
According to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, the reduction of METTL3 decreased the protein level of MMP3, MMP13, and GATA, which are involved in signaling pathways regulating the glycosaminoglycan biosynthesis–chondroitin sulfate/dermatan sulfate and extracellular matrix (ECM)–receptor interaction [124].
m6A modification and key ncRNAs in chondrogenesis of BMSCs (Table 5 and Fig. 5)
MiR-221 is an anti-chondrogenic miRNAs in human mesenchymal stem cells by targeting TRPS1/Mdm2, and silencing this miRNA could contribute to cartilage repair in vivo [126]. Meanwhile, by targeting BMPR2, miR-143-3p also negatively regulates the chondrogenic differentiation of BMSCs [127]. Pri-miRNAs of these two anti-chondrogenic miRNAs could be modulated by METTL3 to encourage the formation of mature miRNAs. DANCR, which could restrain osteogenesis of BMSCs [128–133], is a positive regulator of chondrogenic differentiation by targeting miR-1305, myc, Smad3, STAT3, and Smad4 [134,135]. METTL3 could increase DANCR stability via m6A modification. MEG3 can interact with the miR-129-5p/RUNX1 axis to help BMSCs differentiate into chondrocytes, but the stability of MEG3 RNA was compromised after m6A modification by METTL3 [136].
Activators and Inhibitors Targeting m6A Modification
Less
The development of chemical tools targeting m6A modification (e.g., METTL3 activators/ inhibitors and FTO inhibitors) has aroused considerable interest in treating multiple disorders in the last decade [137,138].
The potency of four small compounds to cooperatively bind to the METTL3 active site and increase its activity was initially described by Selberg and colleagues [139] (Fig. 6A, 1 to 4). In the following cellular assays, compound one was the most effective one, which increased the relative m6A amount by 21.4 ± 12.9% (Fig. 6B). Lan et al. [140] further presented a photo-activatable small-molecule METTL3 agonist (Fig. 6A, 5 and 6), which fully hid its biological activity by obstructing the functional N–H group on the agonist chemical piperidine-3-carboxylate 1 (MPCH 1). However, after being exposed to the 365-nm light for a short while, its activation was effectively restored, leading to a significant hypermethylation of m6A alteration in transcriptome RNAs (Fig. 6C). Dozens of FTO inhibitors have been reported, which can be roughly divided into several types with different structure, binding sites, and binding ability [141]. Given the pro-osteogenic and pro-chondrogenic ability of m6A modification, the application of the METTL3 activators or FTO inhibitors in BMSCs seems to offer hope for promoting bone and cartilage formation in vivo. However, the clinical application of these chemical tools is still in its infancy and there is a lack of investigations about their use in BMSCs.
On the contrary, METTL3-selective inhibitors could occupy the SAM binding site of METTL3 and therefore decrease the m6A level (Fig. 6D). Using a co-factor mimicking approach, reporting from Yankova et al. identified a selective inhibitor (STM2467) of METTL3 catalytic activity with an IC50 (half-maximal inhibitory concentration) of 16.9 nM, and demonstrated its efficacy against myeloid leukemia in vitro and in vivo [142]. STC-15 and UZH1a both serve as METTL3 inhibitors with potential clinical application value in hematological malignancies [143]. Inspired by this, METTL3-selective inhibitor application in BMSCs could be used to treat inflammatory bone diseases.
m6A Modification in Musculoskeletal Disorders
Less
The level of m6A modification in the motor system (namely, the musculoskeletal system) is significantly influenced by a plethora of physical and chemical factors in local environments [144,145]. Xu et al. [144] have compiled a review to summarize the METTL3/METTL14 complex's physiological activities and associated regulation mechanisms in musculoskeletal disorders. However, although there are more than 100 kinds of disorders involving the musculoskeletal system, the investigators only selected four (osteoporosis, rheumatoid arthritis, osteoarthritis, and osteosarcoma) with disparate pathogenesis and regulatory mechanism, and the enrolled studies are mostly basic ones related to METTL3/METTL14.
As shown above, among various kinds of cells in the motor system (e.g., fibroblast, synoviocytes, immune cells, and endothelial cells), the aberrant expression of m6A “writers,” “erasers,” and “readers” in BMSCs disrupts bone and cartilage homeostasis in an m6A-dependent or m6A-independent manner. Based on their role as precursors to osteoblasts, BMSCs are the gold standard for MSC tissue engineering treatment [1,2]. In this section, we sought to shed further light on the expression and function of m6A modification in the onset of osteoporosis, osteomyelitis, bone defects, and osteoarthritis, all of which are characterized by the accelerated deterioration of bone or cartilage [144,145]. Special attention was paid to in vivo studies and the possible application of m6A-based therapy in BMSCs.
Osteoporosis
Osteoporosis is a chronic systemic bone disease characterized by bone loss, occurring concomitant with an accumulation of bone marrow adipocytes [2]. The BMSCs differentiate preferentially toward adipocytes in response to pathogenic stimuli such as hormone abnormalities or aging, which increases bone loss, fracture risk, and marrow adiposity (Fig. 7A) [30]. Peng et al. [105] collected bone marrow from 32 patients with osteoporosis and found that METTL3 was the most significantly down-regulated “writer” in these patients in comparison with healthy volunteers. Consistent results for METTL3 and METTL14 were obtained in osteoporosis animal models (Fig. 7A) [30,31,146,147]. Decreased methylation levels and lower expression of METTL3/METTL14 were revealed in osteoporosis-BMSCs than in BMSCs from the control group [31,52,54]. Cell fate of BMSCs in mice is disrupted by METTL3 or METTL14 deletion, leading to osteoporosis pathological characteristics including decreased bone mass and accumulated marrow adiposity [49,52,54,146,147]. Consistently, the level of FTO is elevated in BMSCs from patients with osteoporosis and ovariectomy (OVX) mouse [34].
As was already indicated, the overexpression of METTL3 and METTL14 partially restored the osteogenic differentiation of BMSCs by the m6A mechanism [30–33,52,54]. Gaining function for METTL3 and METTL14 stops estrogen deficiency-induced postmenopausal osteoporosis [49,54]. These results confirmed that the m6A methylation markedly contributes to the maintenance of osteogenesis as a whole, and overexpression of METTL3 and METTL14 in BMSCs has the potential to become a candidate for treating osteoporosis (Fig. 7B). Meanwhile, OVX-induced osteoporosis in mice with ovariectomies was somewhat mitigated by FTO inhibition [34].
Bone defect
Bone defects occur in many clinical situations such as high-grade open fractures, infection requiring debridement of bone, and resection of bone tumors [148]. For critical-sized bone defects, current treatment options include various natural and synthetic graft materials, such as freeze-dried bone, coral, hydroxylapatite, and tricalcium phosphate [149,150]. In vitro and in vivo investigations have suggested the additional benefits of BMSCs in conjunction with tissue engineering and regenerative medicine in bone repair and regeneration.
The increased osteogenesis of BMSCs by m6A modification could also be used in the treatment of bone defects combined with degradable biomaterials. Compared to the control group, BMSCs stimulated by β-tricalcium phosphate (β-TCP) exhibited considerably greater expression of METTL3, which influences m6A modification of RNA in BMSCs and improves the stability of RUNX2 mRNA [151]. In animal bone defect models, Jiao et al. [151] discovered that β-TCP increased the m6A alteration of RUNX2, which stimulated the production of new bone. Han and colleagues [152] revealed similar results by using mesenchymal stem cells of the apical papillas (SCAPs), odontogenic MSCs with strong osteo/odontogenic capacity. In the nude mouse model transplanted a mixture of SCAPs and HA/tricalcium phosphate as a carrier, miR-196b-5p mimic has favorable effects on the in vivo osteo/odontogenic differentiation of SCAPs in a METTL3-dependent manner [152]. Wu et al. [31] established critical-sized calvarial defects in osteoporosis model rats and implanted biphasic calcium phosphate (BCP) with osteoporosis-BMSCs into the bone defect regions. Eight weeks after transplantation, μ-CT (computed tomography) and H&E (hematoxylin and eosin) staining revealed more bone matrix in the METTL3(+) group than in the METTL3(−) group (Fig. 7C).
Osteomyelitis
As a typical inflammatory bone disease caused by microorganisms, osteomyelitis can lead to progressive bone necrosis, osteolysis, and bone defect [153]. Although antimicrobial therapy and surgery are the primary treatment strategies, interventions to promote bone formation are also indispensable for chronic or progressive osteomyelitis. Hu and Jiao [154] enrolled 33 osteomyelitis patients and demonstrated up-regulated METTL3 expression in the bone marrow puncture tissue samples in comparison with samples from healthy control. However, METTL3 expressed by osteoblasts was down-regulated in lipopolysaccharide (LPS)-induced inflammation and METTL3 depletion favored proinflammatory cytokine expression of osteoblasts [40]. METTL3 was also closely correlated to immune infiltration and immune response of osteomyelitis [153]. The up-regulated METTL3 level could be explained by the enhanced gene expression in immune cells, especially macrophages.
STM2457 pretreatment down-regulated the expression of MyD88 in bone marrow-derived macrophages and alleviated the symptoms of osteomyelitis in mice [154]. Meanwhile, METTL3 knockdown could inhibit osteoclast differentiation and raise osteoclast apoptosis in inflammatory bone disease by promoting NOS2 mRNA stability in a YTHDF1-dependent manner [155]. Nonetheless, it should be highlighted that the blocking of METTL3, on the one hand, avoids the progression of inflammatory osteolysis and destruction and, on the other hand, impedes the osteogenesis of BMSCs and encourages the survival and proliferation of colonized bacteria [154]. The potential therapeutic benefits of STM2457 for osteomyelitis need a further comprehensive analysis.
Osteoarthritis
Osteoarthritis is a chronic, degenerative joint disease characterized by the erosion of joint cartilage and inflammation, as well as degradation of the ECM [156,157]. Chondrocyte is the only type of cell found in cartilage, and the activity of chondrocyte is regulated by multiple inflammatory and metabolic factors [158]. Although METTL3 may help the chondrogenesis of BMSCs, the role of this m6A “writer” in the development of osteoarthritis was debatable [159,160]. According to data from GSE117999, GSE98918, GSE29746, GSE55457, and GSE82107, translation of METTL3 was down-regulated in cartilage, meniscus, and synovial tissues of patients with osteoarthritis in comparison with the normal control [160,161]. Further experiments enrolling 10 patients with osteoarthritis verified these results by using reverse transcription polymerase chain reaction (RT-PCR) and Western blot [160]. Opposite findings were shown in the experimental collagenase-induced osteoarthritis model constructed by Liu et al. [159], which demonstrated an improved METTL3 mRNA level and percentage of m6A methylated mRNA of total mRNA. Two clinical articles also revealed increased expressions of METTL3 mRNA and protein in cartilage of patients with osteoarthritis by using RT-PCR and Western blot [162,163]. However, sample sizes of these two studies are relatively small and whether animal studies could reflect clinical facts remains obscure.
Whether m6A hastens or delays the progression of osteoarthritis is also controversial. Mechanistically, m6A modification up-regulates the expression of LINC00680 in the osteoarthritis tissue and interleukin-1β (IL-1β)-induced isolated primary chondrocytes, and the latter enhances the mRNA stability of SIRT1, a gene with definite functions in osteoarthritis [163]. Meanwhile, METTL3-mediated m6A modification suppresses SOCS2 expression, which activates the JAK2/STAT3 proinflammatory pathway and promotes IL-1β-induced chondrocyte apoptosis, inflammation, and ECM degradation [164]. In contrast, Sang et al.'s [160] study found that METTL3 overexpression decreased the amounts of inflammatory cytokines brought on by IL-1β therapy. From a different angle, m6A modification can regulate ECM breakdown in osteoarthritis by balancing the amounts of MMP1, MMP3, MMP13, TIMP-1, and TIMP-2 [157,160,161].
Conclusion and Future Perspectives
Less
Current studies have revealed that interaction existed between m6A modification, mRNAs, miRNAs, lncRNAs, and other ncRNAs, constructing a complicated network and affecting multiple cellular signaling pathways. By modifying RNA metabolism in m6A-dependent and m6A-independent ways, METTL3 may control the lineage commitment of BMSCs; however, methyltransferase by itself might not be sufficient to determine the direction of differentiation. As a whole, the m6A methylation of RNA positively regulates osteogenesis and chondrogenesis of BMSCs, and reverses adipogenesis, mainly achieved by the direct and indirect regulation of specific TFs. These evidences provide the basis for strengthening m6A modification in specific musculoskeletal disorders. It should be noted that m6A modification is essential for various biological processes, including angiogenesis and bone metabolism [165,166]. To fully comprehend how m6A modification affects each and every BMSC osteogenesis signature, more research is required.
As described earlier, osteoporosis and bone defect are characterized by a disruption of bone homeostasis. m6A modification encourages bone formation and therefore may prevent the progression of these two musculoskeletal conditions. However, the influence of m6A modification on osteomyelitis and osteoarthritis is more convoluted because they are more inflammatory bone diseases besides bone and cartilage destruction. m6A modification may aggravate osteomyelitis and osteoarthritis by controlling the activation of pro-inflammatory immune cells, production of inflammatory mediators, and breakdown of the ECM. Clinical application of METTL3 activators/inhibitors (e.g., STM2457, STC-15, and UZH1α) and FTO inhibitors as therapeutic tools for musculoskeletal disorders is still in its infancy. Meanwhile, since the intact catalytic activity of MTC also relies on the function of METTL14 and other binding partners, m6A modification inhibitors or activators designed on protein–protein interaction strategy also present reasonable options for regulating lineage commitment of BMSCs.
Nevertheless, current understanding of m6A modifications in BMSC differentiation could not be all there is to it. The shortcomings of studies included in this review merit consideration. First, there is controversial evidence about the functions of m6A modifications on ncRNAs in the differentiation of BMSCs and the majority of the current evidence was restricted to in vitro confirmation, rarely in clinical value. A more detailed ceRNA network may be constructed to confirm the interaction between ncRNAs and mRNAs. Second, besides the targets we discussed above, there remain other potential mRNAs and ncRNAs that may be involved in the differentiation of BMSCs. Third, bone and cartilage homeostasis is maintained by various cells and ingredients, and therefore, interventions targeting m6A modifications in BMSCs alone could not so obviously influence these processes. Last but not least, there are not many clinical investigations on the function of m6A modifications in musculoskeletal illnesses.
In this review, we put up novel biological functions and perspectives for the future clinical value of intervening m6A modification in BMSCs as a therapeutic regimen for osteoporosis, osteomyelitis, bone defect, and osteoarthritis. Although these four musculoskeletal disorders are accompanied by the destruction of bone and cartilage, m6A modification contributes to the course of these diseases in both positive and negative ways. More studies are warranted to further investigate the impact of m6A modification on differentiation of BMSCs and verify the efficacy of the m6A modification-based therapy.
Funding
Less
  • China-Japan Friendship Hospital Youth Science and Technology Excellence Project (2022-HX-JC-7)
  • the Young Taishan Scholars Program of Shandong Province(tsqn201909183)
  • Natural Science Foundation of China(82302682)
  • Beijing Natural Science Foundation(7242127)
  • Natural Science Foundation of Shandong Province (ZR2020QH072)
  • Jinan Clinical Medical Science and Technology Innovation Program (202328067)
  • Elite Medical Professionals project of China-Japan Friendship Hospital(ZRJY2021-GG12)
References
Less
1.
Kangari P, Talaei-Khozani T, Razeghian-Jahromi I, Razmkhah M. Mesenchymal stem cells: Amazing remedies for bone and cartilage defects. Stem Cell Res Ther. 2020;11(1):492.
2.
Zhang Q, Dong J, Zhang P, Zhou D, Liu F. Dynamics of transcription factors in three early phases of osteogenic, adipogenic, and chondrogenic differentiation determining the fate of bone marrow mesenchymal stem cells in rats. Front Cell Dev Biol. 2021;9: Article 768316.
3.
Li J, Ma J, Feng Q, Xie E, Meng Q, Shu W, Wu J, Bian L, Han F, Li B. Building osteogenic microenvironments with a double-network composite hydrogel for bone repair. Research. 2023;6:0021.
4.
Bai J, Ge G, Wang Q, Li W, Zheng K, Xu Y, Yang H, Pan G, Geng D. Engineering stem cell recruitment and osteoinduction via bioadhesive molecular mimics to improve osteoporotic bone-implant integration. Research. 2022;2022:9823784.
5.
Liu F, Dong J, Zhou D, Zhang Q. Identification of key candidate genes related to inflammatory osteolysis associated with vitamin e-blended uhmwpe debris of orthopedic implants by integrated bioinformatics analysis and experimental confirmation. J Inflamm Res. 2021;14:3537–3554.
6.
Chen G, Zhuo Y, Tao B, Liu Q, Shang W, Li Y, Wang Y, Li Y, Zhang L, Fang Y, et al. Moderate SMFs attenuate bone loss in mice by promoting directional osteogenic differentiation of BMSCs. Stem Cell Res Ther. 2020;11(1):487.
7.
Liu F, Dong J, Zhang P, Zhou D, Zhang Q. Transcriptome sequencing reveals key genes in three early phases of osteogenic, adipogenic, and chondrogenic differentiation of bone marrow mesenchymal stem cells in rats. Front Mol Biosci. 2021;8: Article 782054.
8.
Hung S-P, Ho JH, Shih Y-RV, Lo T, Lee OK. Hypoxia promotes proliferation and osteogenic differentiation potentials of human mesenchymal stem cells. J Orthop Res. 2012;30(2):260–266.
9.
Huang W, Chen T-Q, Fang K, Zeng Z-C, Ye H, Chen Y-Q. N6-methyladenosine methyltransferases: Functions, regulation, and clinical potential. J Hematol Oncol. 2021;14(1):117.
10.
Xu P, Ge R. Roles and drug development of METTL3 (methyltransferase-like 3) in anti-tumor therapy. Eur J Med Chem. 2022;230: Article 114118.
11.
Ma C, Ma R-J, Hu K, Zheng Q-M, Wang Y-P, Zhang N, Sun Z-G. The molecular mechanism of METTL3 promoting the malignant progression of lung cancer. Cancer Cell Int. 2022;22(1):133.
12.
Li G, Sun Z, Deng W, Cheng S, Liu X, Liu J, Tang X, Zhang Z. METTL3 plays a crucial function in multiple biological processes. Acta Histochem. 2022;124(6): Article 151916.
13.
Wu X, Ye W, Gong Y. The role of RNA methyltransferase METTL3 in normal and malignant hematopoiesis. Front Oncol. 2022;12: Article 873903.
14.
Mei Z, Mou Y, Zhang N, Liu X, He Z, Gu S. Emerging mutual regulatory roles between m6A modification and microRNAs. Int J Mol Sci. 2023;24(1):773.
15.
Han X, Guo J, Fan Z. Interactions between m6A modification and miRNAs in malignant tumors. Cell Death Dis. 2021;12(6):598.
16.
Zhang N, Sun Y, Mei Z, He Z, Gu S. Novel insights into mutual regulation between N6-methyladenosine modification and LncRNAs in tumors. Cancer Cell Int. 2023;23(1):127.
17.
Roberts SB, Wootton E, De Ferrari L, Albagha OM, Salter DM. Epigenetics of osteoarticular diseases: Recent developments. Rheumatol Int. 2015;35(8):1293–1305.
18.
Luo G, Chen J, Ren Z. Regulation of methylase METTL3 on fat deposition. Diabetes Metab Syndr Obes. 2021;14:4843–4852.
19.
Zeng C, Huang W, Li Y, Weng H. Roles of METTL3 in cancer: Mechanisms and therapeutic targeting. J Hematol Oncol. 2020;13(1):117.
20.
Wang S, Lv W, Li T, Zhang S, Wang H, Li X, Wang L, Ma D, Zang Y, Shen J, et al. Dynamic regulation and functions of mRNA m6A modification. Cancer Cell Int. 2022;22(1):48.
21.
Li D, Cai L, Meng R, Feng Z, Xu Q. METTL3 modulates osteoclast differentiation and function by controlling RNA stability and nuclear export. Int J Mol Sci. 2020;21(5):1660.
22.
Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, Weng X, Chen K, Shi H, He C. N6-methyladenosine modulates messenger RNA translation efficiency. Cell. 2015;161(6):1388–1399.
23.
Choe J, Lin S, Zhang W, Liu Q, Wang L, Ramirez-Moya J, Du P, Kim W, Tang S, Sliz P, et al. mRNA circularization by METTL3-eiF3h enhances translation and promotes oncogenesis. Nature. 2018;561(7724):556–560.
24.
Lan Y, Liu B, Guo H. The role of m6A modification in the regulation of tumor-related lncRNAs. Mol Ther Nucleic Acids. 2021;24:768–779.
25.
He RZ, Jiang J, Luo DX. The functions of n6-methyladenosine modification in lncRNAs. Genes Dis. 2020;7(4):598–605.
26.
Shen W, Zhu M, Wang Q, Zhou X, Wang J, Wang T, Zhang J. DARS-AS1 recruits METTL3/METTL14 to bind and enhance DARS mRNA m6A modification and translation for cytoprotective autophagy in cervical cancer. RNA Biol. 2022;19(1):751–763.
27.
Alarcón CR, Lee H, Goodarzi H, Halberg N, Tavazoie SF. N6-methyladenosine marks primary microRNAs for processing. Nature. 2015;519(7544):482–485.
28.
Wang H, Deng Q, Lv Z, Ling Y, Hou X, Chen Z, Dinglin X, Ma S, Li D, Wu Y, et al. N6-methyladenosine induced miR-143-3p promotes the brain metastasis of lung cancer via regulation of VASH1. Mol Cancer. 2019;18(1):181.
29.
Yang Y, Song S, Meng Q, Wang L, Li X, Xie S, Chen Y, Jiang X, Wang C, Lu Y, et al. miR24-2 accelerates progression of liver cancer cells by activating Pim1 through tri-methylation of histone H3 on the ninth lysine. J Cell Mol Med. 2020;24(5):2772–2790.
30.
Yan G, Yuan Y, He M, Gong R, Lei H, Zhou H, Wang W, Du W, Ma T, Liu S, et al. m6A methylation of precursor-miR-320/RUNX2 controls osteogenic potential of bone marrow-derived mesenchymal stem cells. Mol Ther Nucleic Acids. 2020;19:421–436.
31.
Wu T, Tang H, Yang J, Yao Z, Bai L, Xie Y, Li Q, Xiao J. METTL3-m6A methylase regulates the osteogenic potential of bone marrow mesenchymal stem cells in osteoporotic rats via the Wnt signalling pathway. Cell Prolif. 2022;55(5): Article e13234.
32.
Li L, Wang B, Zhou X, Ding H, Sun C, Wang Y, Zhang F, Zhao J. METTL3-mediated long non-coding RNA MIR99AHG methylation targets miR-4660 to promote bone marrow mesenchymal stem cell osteogenic differentiation. Cell Cycle. 2023;22(4):476–493.
33.
Zhou S, Zhang G, Wang K, Yang Z, Tan Y. METTL3 potentiates osteogenic differentiation of bone marrow mesenchymal stem cells via IGF2BP1/m6A/RUNX2. Oral Dis. 2023.
34.
Wang J, Fu Q, Yang J, Liu JL, Hou SM, Huang X, Cao JS, Liu TL, Wang KZ. RNA n6-methyladenosine demethylase FTO promotes osteoporosis through demethylating Runx2 mRNA and inhibiting osteogenic differentiation. Aging. 2021;13(17):21134–21141.
35.
Chen L-S, Zhang M, Chen P, Xiong X-F, Liu P-Q, Wang H-B, Wang J-J, Shen J. The m6A demethylase FTO promotes the osteogenesis of mesenchymal stem cells by downregulating PPARG. Acta Pharmacol Sin. 2022;43(5):1311–1323.
36.
Yu J, Shen L, Liu Y, Ming H, Zhu X, Chu M, Lin J. The m6A methyltransferase METTL3 cooperates with demethylase ALKBH5 to regulate osteogenic differentiation through NF-κB signaling. Mol Cell Biochem. 2020;463(1-2):203–210.
37.
Li Z, Wang P, Li J, Xie Z, Cen S, Li M, Liu W, Ye G, Zheng G, Ma M, et al. The N6-methyladenosine demethylase ALKBH5 negatively regulates the osteogenic differentiation of mesenchymal stem cells through PRMT6. Cell Death Dis. 2021;12(6):578.
38.
Gao Q, Wang L, Wang S, Huang B, Jing Y, Su J. Bone marrow mesenchymal stromal cells: Identification, classification, and differentiation. Front Cell Dev Biol. 2021;9: Article 787118.
39.
Lin W, Zhu X, Gao L, Mao M, Gao D, Huang Z. Osteomodulin positively regulates osteogenesis through interaction with BMP2. Cell Death Dis. 2021;12(2):147.
40.
Zhang Y, Gu X, Li D, Cai L, Xu Q. METTL3 regulates osteoblast differentiation and inflammatory response via Smad signaling and MAPK signaling. Int J Mol Sci. 2019;21(1):199.
41.
Franceschi RT, Xiao G, Jiang D, Gopalakrishnan R, Yang S, Reith E. Multiple signaling pathways converge on the Cbfa1/Runx2 transcription factor to regulate osteoblast differentiation. Connect Tissue Res. 2003;44(Suppl 1):109–116.
42.
Zhou S, Chen S, Jiang Q, Pei M. Determinants of stem cell lineage differentiation toward chondrogenesis versus adipogenesis. Cell Mol Life Sci. 2019;76(9):1653–1680.
43.
Komori T. Regulation of skeletal development by the Runx family of transcription factors. J Cell Biochem. 2005;95(3):445–453.
44.
Liu J, Chen M, Ma L, Dang X, Du G. piRNA-36741 regulates BMP2-mediated osteoblast differentiation via METTL3 controlled m6A modification. Aging. 2021;13(19):23361–23375.
45.
Liu Y, Berendsen AD, Jia S, Lotinun S, Baron R, Ferrara N, Olsen BR. Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation. J Clin Invest. 2012;122(9):3101–3113.
46.
Tian C, Huang Y, Li Q, Feng Z, Xu Q. Mettl3 regulates osteogenic differentiation and alternative splicing of Vegfa in bone marrow mesenchymal stem cells. Int J Mol Sci. 2019;20(3):551.
47.
Rashid H, Ma C, Chen H, Wang H, Hassan MQ, Sinha K, de Crombrugghe B, Javed A. Sp7 and Runx2 molecular complex synergistically regulate expression of target genes. Connect Tissue Res. 2014;55 (0 1):83–87.
48.
Matsubara T, Kida K, Yamaguchi A, Hata K, Ichida F, Meguro H, Aburatani H, Nishimura R, Yoneda T. Bmp2 regulates osterix through Msx2 and Runx2 during osteoblast differentiation. J Biol Chem. 2008;283(43):29119–29125.
49.
Wu Y, Xie L, Wang M, Xiong Q, Guo Y, Liang Y, Li J, Sheng R, Deng P, Wang Y, et al. Mettl3-mediated m6A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis. Nat Commun. 2018;9(1):4772.
50.
Guo Z, Wang Z, Liu Y, Wu H, Zhang Q, Han J, Liu J, Zhang C. Carbon dots from Lycium barbarum attenuate radiation-induced bone injury by inhibiting senescence via METTL3/Clip3 in an m6A-dependent manner. ACS Appl Mater Interfaces. 2023;15(17):20726–20741.
51.
Cheng C, Zhang H, Zheng J, Jin Y, Wang D, Dai Z. METTL14 benefits the mesenchymal stem cells in patients with steroid-associated osteonecrosis of the femoral head by regulating the m6A level of PTPN6. Aging. 2021;13(24):25903–25919.
52.
Wang X, Zou C, Li M, Hou C, Jiang W, Bian Z, Zhu L. METTL14 upregulates TCF1 through m6A mRNA methylation to stimulate osteogenic activity in osteoporosis. Hum Cell. 2023;36(1):178–194.
53.
He M, Lei H, He X, Liu Y, Wang A, Ren Z, Liu X, Yan G, Wang W, Wang Y, et al. METTL14 regulates osteogenesis of bone marrow mesenchymal stem cells via inducing autophagy through m6A/IGF2BPs/beclin-1 signal axis. Stem Cells Transl Med. 2022;11(9):987–1001.
54.
Huang C, Wang Y. Downregulation of METTL14 improves postmenopausal osteoporosis via iGF2BP1 dependent posttranscriptional silencing of SMAD1. Cell Death Dis. 2022;13(11):919.
55.
Liu E, Lv L, Zhan Y, Ma Y, Feng J, He Y, Wen Y, Zhang Y, Pu Q, Ji F, et al. METTL3/N6-methyladenosine/ miR-21-5p promotes obstructive renal fibrosis by regulating inflammation through SPRY1/ERK/NF-κB pathway activation. J Cell Mol Med. 2021;25(16):7660–7674.
56.
Li X, Guo L, Liu Y, Su Y, Xie Y, Du J, Zhou J, Ding G, Wang H, Bai Y, et al. MicroRNA-21 promotes osteogenesis of bone marrow mesenchymal stem cells via the Smad7-Smad1/5/8-Runx2 pathway. Biochem Biophys Res Commun. 2017;493(2):928–933.
57.
Yang C, Liu X, Zhao K, Zhu Y, Hu B, Zhou Y, Wang M, Wu Y, Zhang C, Xu J, et al. miRNA-21 promotes osteogenesis via the PTEN/PI3K/Akt/HIF-1α pathway and enhances bone regeneration in critical size defects. Stem Cell Res Ther. 2019;10(1):65.
58.
Liu J, You Y, Sun Z, Zhang L, Li X, Dai Z, Ma J, Chen Y, Jiao G. WTAP-mediated m6A RNA methylation regulates the differentiation of bone marrow mesenchymal stem cells via the miR-29b-3p/HDAC4 axis. Stem Cells Transl Med. 2023;12(5):307–321.
59.
You Y, Liu J, Zhang L, Li X, Sun Z, Dai Z, Ma J, Jiao G, Chen Y. WTAP-mediated m6A modification modulates bone marrow mesenchymal stem cells differentiation potential and osteoporosis. Cell Death Dis. 2023;14(1):33.
60.
Dong X, Liao B, Zhao J, Li X, Yan K, Ren K, Zhang X, Bao X, Guo W. METTL14 mediates m6A modification on osteogenic proliferation and differentiation of bone marrow mesenchymal stem cells by regulating the processing of pri-miR-873. Mol Med Rep. 2023;28(3):166.
61.
Wangzhou K, Lai Z, Lu Z, Fu W, Liu C, Liang Z, Tan Y, Li C, Hao C. MiR-143-3p inhibits osteogenic differentiation of human periodontal ligament cells by targeting KLF5 and inactivating the Wnt/β-catenin pathway. Front Physiol. 2020;11: Article 606967.
62.
Wu L, Song J, Xue J, Xiao T, Wei Q, Zhang Z, Zhang Y, Li Z, Hu Y, Zhang G, et al. MircoRNA-143-3p regulating ARL6 is involved in the cadmium-induced inhibition of osteogenic differentiation in human bone marrow mesenchymal stem cells. Toxicol Lett. 2020;331:159–166.
63.
Yang C, Xu X, Lin P, Luo B, Luo S, Huang H, Zhu J, Huang M, Peng S, Wu Q, et al. Overexpression of long noncoding RNA MCM3AP-AS1 promotes osteogenic differentiation of dental pulp stem cells via miR-143-3p/IGFBP5 axis. Hum Cell. 2022;35(1):150–162.
64.
Gao S, Ge L-H, Zhao Y-M, Li P, Li Y-Y, Zhao W. Hsa-miRNA-143-3p regulates the odontogenic differentiation of human stem cells from the apical papilla by targeting NFIC. Int Endod J. 2022;55(3):263–274.
65.
Sun J, Zhang F, Luo X, Shi G, Li F, Zheng B, Guo Y, Shi J, Li L. Long noncoding RNA AC092155 facilitates osteogenic differentiation of adipose-derived stem cells through the miR-143-3p/STMN1 axis. J Gene Med. 2021;23(8): Article e3363.
66.
Wang P, Wang Z, Zhang M, Wu Q, Shi F, Yuan S. KIAA1429 and ALKBH5 oppositely influence aortic dissection progression via regulating the maturation of pri-miR-143-3p in an m6A-dependent manner. Front Cell Dev Biol. 2021;9: Article 668377.
67.
Qian K, Xu W, Xia X, Ding J. Methyltransferase-like 3 (METTL3) mediated N6-methyladenosine (m6A) modifications facilitate mir-25-3p maturation to promote gastrointestinal stromal tumors (GISTs) progression. Genes Genomics. 2022;44:1519–1530.
68.
Zha X, Xi X, Fan X, Ma M, Zhang Y, Yang Y. Overexpression of METTL3 attenuates high-glucose induced RPE cell pyroptosis by regulating miR-25-3p/PTEN/AKt signaling cascade through DGCR8. Aging. 2020;12(9):8137–8150.
69.
Zhang J, Bai R, Li M, Ye H, Wu C, Wang C, Li S, Tan L, Mai D, Li G, et al. Excessive miR-25-3p maturation via N6-methyladenosine stimulated by cigarette smoke promotes pancreatic cancer progression. Nat Commun. 2019;10(1):1858.
70.
Yu D, Li Z, Cao J, Shen F, Wei G. MicroRNA-25-3p suppresses osteogenic differentiation of BMSCs in patients with osteoporosis by targeting ITGB3. Acta Histochem. 2022;124(6): Article 151926.
71.
Cao L, Liu W, Zhong Y, Zhang Y, Gao D, He T, Liu Y, Zou Z, Mo Y, Peng S, et al. Linc02349 promotes osteogenesis of human umbilical cord-derived stem cells by acting as a competing endogenous RNA for miR-25-3p and miR-33b-5p. Cell Prolif. 2020;53(5): Article e12814.
72.
Cheng D, Wu C, Li Y, Liu Y, Mo J, Fu L, Peng S. METTL3 inhibition ameliorates liver damage in mouse with hepatitis B virus-associated acute-on-chronic liver failure by regulating miR-146a-5p maturation. Biochim Biophys Acta Gene Regul Mech. 2022;1865(3): Article 194782.
73.
Yan R, Dai W, Wu R, Huang H, Shu M. Therapeutic targeting m6A-guided miR-146a-5p signaling contributes to the melittin-induced selective suppression of bladder cancer. Cancer Lett. 2022;534: Article 215615.
74.
Zheng M, Tan J, Liu X, Jin F, Lai R, Wang X. MiR-146a-5p targets Sirt1 to regulate bone mass. Bone Rep. 2021;14: Article 101013.
75.
Gong W-J, Li R, Dai Q-Q, Yu P. METTL3 contributes to slow transit constipation by regulating miR-30b-5p/PIK3R2/Akt/mTOR signaling cascade through DGCR8. J Gastroenterol Hepatol. 2022;37(12):2229–2242.
76.
Luo Y, Zhou F, Wu X, Li Y, Ye B. MiR-30b-5p inhibits osteoblast differentiation through targeting BCL6. Cell Cycle. 2022;21(6):630–640.
77.
Sun M, Shen Y, Jia G, Deng Z, Shi F, Jing Y, Xia S. Activation of the HNRNPA2B1/miR-93-5p/FRMD6 axis facilitates prostate cancer progression in an m6A-dependent manner. J Cancer. 2023;14(7):1242–1256.
78.
Zhang Y, Wei Q-S, Ding W-B, Zhang L-L, Wang H-C, Zhu Y-J, He W, Chai Y-N, Liu Y-W. Increased microRNA-93-5p inhibits osteogenic differentiation by targeting bone morphogenetic protein-2. PLOS ONE. 2017;12(8): Article e182678.
79.
Chen J, Lai K, Yong X, Yin H, Chen Z, Wang H, Chen K, Zheng J. Silencing METTL3 stabilizes atherosclerotic plaques by regulating the phenotypic transformation of vascular smooth muscle cells via the miR-375-3p/PDK1 axis. Cardiovasc Drugs Ther. 2023;37(3):471–486.
80.
Sun T, Li C-T, Xiong L, Ning Z, Leung F, Peng S, Lu WW. MiR-375-3p negatively regulates osteogenesis by targeting and decreasing the expression levels of LRP5 and β-catenin. PLOS ONE. 2017;12(2): Article e171281.
81.
Zhang R, Qu Y, Ji Z, Hao C, Su Y, Yao Y, Zuo W, Chen X, Yang M, Ma G. METTL3 mediates Ang-ii-induced cardiac hypertrophy through accelerating pri-miR-221/222 maturation in an m6A-dependent manner. Cell Mol Biol Lett. 2022;27(1):55.
82.
Zhang Y, Gao Y, Cai L, Li F, Lou Y, Xu N, Kang Y, Yang H. MicroRNA-221 is involved in the regulation of osteoporosis through regulates RUNX2 protein expression and osteoblast differentiation. Am J Transl Res. 2017;9(1):126–135.
83.
Gan K, Dong G-H, Wang N, Zhu J-F. MiR-221-3p and miR-222-3p downregulation promoted osteogenic differentiation of bone marrow mesenchyme stem cells through IGF-1/ERK pathway under high glucose condition. Diabetes Res Clin Pract. 2020;167: Article 108121.
84.
Fan F-Y, Deng R, Lai S-H, Wen Q, Zeng Y, Gao L, Liu Y, Kong P, Zhong J, Su Y, et al. Inhibition of microRNA-221-5p induces osteogenic differentiation by directly targeting smad3 in myeloma bone disease mesenchymal stem cells. Oncol Lett. 2019;18(6):6536–6544.
85.
Xiao X, Zhou T, Guo S, Guo C, Zhang Q, Dong N, Wang Y. LncRNA MALAT1 sponges miR-204 to promote osteoblast differentiation of human aortic valve interstitial cells through up-regulating Smad4. Int J Cardiol. 2017;243:404–412.
86.
Gao Y, Xiao F, Wang C, Wang C, Cui P, Zhang X, Chen X. Long noncoding RNA MALAT1 promotes osterix expression to regulate osteogenic differentiation by targeting miRNA-143 in human bone marrow-derived mesenchymal stem cells. J Cell Biochem. 2018;119(8):6986–6996.
87.
Chang Y-Z, Chai R-C, Pang B, Chang X, An SY, Zhang K-N, Jiang T, Wang Y-Z. METTL3 enhances the stability of MALAT1 with the assistance of HuR via m6A modification and activates NF-κB to promote the malignant progression of IDH-wildtype glioma. Cancer Lett. 2021;511:36–46.
88.
Yao F-Y, Zhao C, Zhong F-M, Qin T-Y, Wen F, Li M-Y, Liu J, Huang B, Wang X-Z. m6A modification of lncRNA NEAT1 regulates chronic myelocytic leukemia progression via miR-766-5p/CDKN1A axis. Front Oncol. 2021;11: Article 679634.
89.
Zhang Y, Chen B, Li D, Zhou X, Chen Z. LncRNA NEAT1/miR-29b-3p/BMP1 axis promotes osteogenic differentiation in human bone marrow-derived mesenchymal stem cells. Pathol Res Pract. 2019;215(3):525–531.
90.
Bian W, Xiao S, Yang L, Chen J, Deng S. Quercetin promotes bone marrow mesenchymal stem cell proliferation and osteogenic differentiation through the H19/miR-625-5p axis to activate the Wnt/β-catenin pathway. BMC Complement Med Ther. 2021;21(1):243.
91.
Han H, Tian T, Huang G, Li D, Yang S. The lncRNA H19/miR-541-3p/Wnt/β-catenin axis plays a vital role in melatonin-mediated osteogenic differentiation of bone marrow mesenchymal stem cells. Aging. 2021;13(14):18257–18273.
92.
Ma X, Bian Y, Yuan H, Chen N, Pan Y, Zhou W, Gao S, Du X, Hao S, Yan Z, et al. Human amnion-derived mesenchymal stem cells promote osteogenic differentiation of human bone marrow mesenchymal stem cells via H19/miR-675/APC axis. Aging. 2020;12(11):10527–10543.
93.
Liang W-C, Fu W-M, Wang Y-B, Sun Y-X, Xu L-L, Wong C-W, Chan K-M, Li G, Waye MM-M, Zhang J-F. H19 activates Wnt signaling and promotes osteoblast differentiation by functioning as a competing endogenous RNA. Sci Rep. 2016;6:20121.
94.
He Q, Li R, Hu B, Li X, Wu Y, Sun P, Jia Y, Guo Y. Stromal cell-derived factor-1 promotes osteoblastic differentiation of human bone marrow mesenchymal stem cells via the lncRNA-H19/miR-214-5p/BMP2 axis. J Gene Med. 2021;23(9): Article e3366.
95.
Li T, Jiang H, Li Y, Zhao X, Ding H. Estrogen promotes lncRNA H19 expression to regulate osteogenic differentiation of BMSCs and reduce osteoporosis via miR-532-3p/SIRT1 axis. Mol Cell Endocrinol. 2021;527: Article 111171.
96.
Wang Y, Liu W, Liu Y, Cui J, Zhao Z, Cao H, Fu Z, Liu B. Long noncoding RNA H19 mediates LCoR to impact the osteogenic and adipogenic differentiation of mBMSCS in mice through sponging miR-188. J Cell Physiol. 2018;233(9):7435–7446.
97.
Li G, Yun X, Ye K, Zhao H, An J, Zhang X, Han X, Li Y, Wang S. Long non-coding RNA-H19 stimulates osteogenic differentiation of bone marrow mesenchymal stem cells via the microRNA-149/SDF-1 axis. J Cell Mol Med. 2020;24(9):4944–4955.
98.
Bi HU, Wang D, Liu X, Wang G, Wu X. Long non-coding RNA H19 promotes osteogenic differentiation of human bone marrow-derived mesenchymal stem cells by regulating microRNA-140-5p/SATB2 axis. J Biosci. 2020;45:–56.
99.
Wu J, Zhao J, Sun L, Pan Y, Wang H, Zhang W-B. Long non-coding RNA H19 mediates mechanical tension-induced osteogenesis of bone marrow mesenchymal stem cells via FAK by sponging miR-138. Bone. 2018;108:62–70.
100.
Xiaoling G, Shuaibin L, Kailu L. MicroRNA-19b-3p promotes cell proliferation and osteogenic differentiation of BMSCs by interacting with lncRNA H19. BMC Med Genet. 2020;21(1):11.
101.
Zhou Z, Hossain MS, Liu D. Involvement of the long noncoding RNA H19 in osteogenic differentiation and bone regeneration. Stem Cell Res Ther. 2021;12(1):74.
102.
Su Y, Xu R, Zhang R, Qu Y, Zuo W, Ji Z, Geng H, Pan M, Ma G. N6-methyladenosine methyltransferase plays a role in hypoxic preconditioning partially through the interaction with lncRNA H19. Acta Biochim Biophys Sin. 2020;52(12):1306–1315.
103.
Guo B, Zhu X, Li X, Yuan CF. The roles of LncRNAs in osteogenesis, adipogenesis and osteoporosis. Curr Pharm Des. 2021;27(1):91–104.
104.
Huang Y, Zheng Y, Jia L, Li W. Long noncoding RNA H19 promotes osteoblast differentiation via TGF-β1/Smad3/HDAC signaling pathway by deriving miR-675. Stem Cells. 2015;33(12):3481–3492.
105.
Peng J, Zhan Y, Zong Y. METTL3-mediated LINC00657 promotes osteogenic differentiation of mesenchymal stem cells via miR-144-3p/BMPR1B axis. Cell Tissue Res. 2022;388(2):301–312.
106.
Pan Z-P, Wang B, Hou D-Y, You R-L, Wang X-T, Xie W-H, Huang H-F. METTL3 mediates bone marrow mesenchymal stem cell adipogenesis to promote chemoresistance in acute myeloid leukaemia. FEBS Open Bio. 2021;11(6):1659–1672.
107.
Xu D, Gao Y, Hu N, Wu L, Chen Q. MiR-365 ameliorates dexamethasone-induced suppression of osteogenesis in MC3T3-E1 cells by targeting HDAC4. Int J Mol Sci. 2017;18(5):977.
108.
Chen Q, Shou P, Zheng C, Jiang M, Cao G, Yang Q, Cao J, Xie N, Velletri T, Zhang X, et al. Fate decision of mesenchymal stem cells: Adipocytes or osteoblasts? Cell Death Differ. 2016;23(7):1128–1139.
109.
Yao Y, Bi Z, Wu R, Zhao Y, Liu Y, Liu Q, Wang Y, Wang X. METTL3 inhibits BMSC adipogenic differentiation by targeting the JAK1/STAT5/C/EBPβ pathway via an m6A-YTHDF2-dependent manner. FASEB J. 2019;33(6):7529–7544.
110.
Yang Z, Yu G-L, Zhu X, Peng T-H, Lv Y-C. Critical roles of FTO-mediated mRNA m6A demethylation in regulating adipogenesis and lipid metabolism: Implications in lipid metabolic disorders. Genes Dis. 2022;9(1):51–61.
111.
Lee J-E, Schmidt H, Lai B, Ge K. Transcriptional and epigenomic regulation of adipogenesis. Mol Cell Biol. 2019;39(11):e00601–e00618.
112.
Rosen ED, Hsu C-H, Wang X, Sakai S, Freeman MW, Gonzalez FJ, Spiegelman BM. C/EBPα induces adipogenesis through PPARγ: A unified pathway. Genes Dev. 2002;16(1):22–26.
113.
Wu R, Guo G, Bi Z, Liu Y, Zhao Y, Chen N, Wang F, Wang Y, Wang X. m6A methylation modulates adipogenesis through JAK2-STAT3-C/EBPβ signaling. Biochim Biophys Acta Gene Regul Mech. 2019;1862(8):796–806.
114.
Shen G-S, Zhou H-B, Zhang H, Chen B, Liu Z-P, Yuan Y, Zhou X-Z, Xu Y-J. The GDF11-FTO-PPARγ axis controls the shift of osteoporotic MSC fate to adipocyte and inhibits bone formation during osteoporosis. Biochim Biophys Acta Mol Basis Dis. 2018;1864(12):3644–3654.
115.
Liu Q, Zhao Y, Wu R, Jiang Q, Cai M, Bi Z, Liu Y, Yao Y, Feng J, Wang Y, et al. ZFP217 regulates adipogenesis by controlling mitotic clonal expansion in a METTL3-m6A dependent manner. RNA Biol. 2019;16(12):1785–1793.
116.
Hu N, Zou L, Wang C, Song G. RUNX1T1 function in cell fate. Stem Cell Res Ther. 2022;13(1):369.
117.
Zhao X, Yang Y, Sun BF, Shi Y, Yang X, Xiao W, Hao Y-J, Ping X-L, Chen Y-S, Wang W-J, et al. FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Res. 2014;24(12):1403–1419.
118.
Wu R, Liu Y, Yao Y, Zhao Y, Bi Z, Jiang Q, Liu Q, Cai M, Wang F, Wang Y, et al. FTO regulates adipogenesis by controlling cell cycle progression via m6A-YTHDF2 dependent mechanism. Biochim Biophys Acta Mol Cell Biol Lipids. 2018;1863(10):1323–1330.
119.
Yamaguchi S, Zhang D, Katayama A, Kurooka N, Sugawara R, Albuayjan H, Nakatsuka A, Eguchi J, Wada J. Adipocyte-specific inhibition of Mir221/222 ameliorates diet-induced obesity through targeting Ddit4. Front Endocrinol. 2021;12: Article 750261.
120.
Li Z, Jin C, Chen S, Zheng Y, Huang Y, Jia L, Ge W, Zhou Y. Long non-coding RNA MEG3 inhibits adipogenesis and promotes osteogenesis of human adipose-derived mesenchymal stem cells via miR-140-5p. Mol Cell Biochem. 2017;433(1-2):51–60.
121.
Li Y, Yang F, Gao M, Gong R, Jin M, Liu T, Sun Y, Fu Y, Huang Q, Zhang W, et al. MiR-149-3p regulates the switch between adipogenic and osteogenic differentiation of BMSCs by targeting FTO. Mol Ther Nucleic Acids. 2019;17:590–600.
122.
Chen S, Song P, Wang Y, Wang Z, Xue J, Jiang Y, Zhou Y, Zhao J, Tang L. CircMAPK9 promotes adipogenesis through modulating hsa-miR-1322/FTO axis in obesity. iScience. 2023;26(10): Article 107756.
123.
Yang L, Ren Z, Yan S, Zhao L, Liu J, Zhao L, Li Z, Ye S, Liu A, Li X, et al. Nsun4 and Mettl3 mediated translational reprogramming of Sox9 promotes BMSC chondrogenic differentiation. Commun Biol. 2022;5(1):495.
124.
Hu B, Zou X, Yu Y, Jiang Y, Xu H. METTL3 promotes SMSCs chondrogenic differentiation by targeting the MMP3, MMP13, and GATA3. Regen Ther. 2023;22:148–159.
125.
Lefebvre V, Dvir-Ginzberg M. SOX9 and the many facets of its regulation in the chondrocyte lineage. Connect Tissue Res. 2017;58(1):2–14.
126.
Lolli A, Narcisi R, Lambertini E, Penolazzi L, Angelozzi M, Kops N, Gasparini S, van Osch GJ, Piva R. Silencing of antichondrogenic microRNA-221 in human mesenchymal stem cells promotes cartilage repair in vivo. Stem Cells. 2016;34(7):1801–1811.
127.
Tian J, Rui Y-J, Xu Y-J, Zhang S-A. MiR-143-3p regulates early cartilage differentiation of BMSCs and promotes cartilage damage repair through targeting BMPR2. Eur Rev Med Pharmacol Sci. 2018;22(24):8814–8821.
128.
Chen L, Song Z, Huang S, Wang R, Qin W, Guo J, Lin Z. LncRNA DANCR suppresses odontoblast-like differentiation of human dental pulp cells by inhibiting Wnt/β-catenin pathway. Cell Tissue Res. 2016;364(2):309–318.
129.
Weng W, Di S, Xing S, Sun Z, Shen Z, Dou X, He S, Tang H, Min J. Long non-coding RNA DANCR modulates osteogenic differentiation by regulating the miR-1301-3p/PROX1 axis. Mol Cell Biochem. 2021;476(6):2503–2512.
130.
Wang CG, Hu YH, Su SL, Zhong D. LncRNA DANCR and miR-320a suppressed osteogenic differentiation in osteoporosis by directly inhibiting the Wnt/β-catenin signaling pathway. Exp Mol Med. 2020;52(8):1310–1325.
131.
Zhu L, Xu PC. Downregulated LncRNA-ANCR promotes osteoblast differentiation by targeting EZH2 and regulating Runx2 expression. Biochem Biophys Res Commun. 2013;432(4):612–617.
132.
Zhang J, Tao Z, Wang Y. Long noncoding RNA DANCR regulates the proliferation and osteogenic differentiation of human bone-derived marrow mesenchymal stem cells via the p38 MAPK pathway. Int J Mol Med. 2018;41(1):213–219.
133.
Zhou X, Yang Y, Li Y, Liang G, Kang D, Zhou B, Li Q. METTL3 contributes to osteosarcoma progression by increasing DANCR MRNA stability via m6A modification. Front Cell Dev Biol. 2021;9: Article 784719.
134.
Zhang L, Sun X, Chen S, Yang C, Shi B, Zhou L, Zhao J. Long noncoding RNA DANCR regulates miR-1305-Smad 4 axis to promote chondrogenic differentiation of human synovium-derived mesenchymal stem cells. Biosci Rep. 2017;37(4):BSR20170347.
135.
Zhang L, Yang C, Chen S, Wang G, Shi B, Tao X, Zhou L, Zhao J. Long noncoding RNA DANCR is a positive regulator of proliferation and chondrogenic differentiation in human synovium-derived stem cells. DNA Cell Biol. 2017;36(2):136–142.
136.
Wu J, Pang R, Li M, Chen B, Huang J, Zhu Y. m6A-induced LncRNA MEG3 suppresses the proliferation, migration and invasion of hepatocellular carcinoma cell through miR-544b/BTG2 signaling. Onco Targets Ther. 2021;14:3745–3755.
137.
Deng L-J, Deng W-Q, Fan S-R, Chen M-F, Qi M, Lyu W-Y, Qi Q, Tiwari AK, Chen J-X, Zhang D-M, et al. m6A modification: Recent advances, anticancer targeted drug discovery and beyond. Mol Cancer. 2022;21(1):52.
138.
Ofir-Rosenfeld Y, Vasiliauskaitė L, Saunders C, Sapetschnig A, Tsagkogeorga G, Albertella M, Carkill M, Self-Fordham J, Holz JB, Rausch O. STC-15, an oral small molecule inhibitor of the RNA methyltransferase METTL3, inhibits tumour growth through activation of anti-cancer immune responses associated with increased interferon signalling, and synergises with T cell checkpoint blockade. Eur J Cancer. 2022;174:S123.
139.
Selberg S, Blokhina D, Aatonen M, Koivisto P, Siltanen A, Mervaala E, Kankuri E, Karelson M. Discovery of small molecules that activate RNA methylation through cooperative binding to the METTL3-14-WTAP complex active site. Cell Rep. 2019;26(13):3762–3771.
140.
Lan L, Sun Y-J, Jin X-Y, Xie L-J, Liu L, Cheng L. A light-controllable chemical modulation of m6A RNA methylation. Angew Chem Int Ed Engl. 2021;60(33):18116–18121.
141.
Gao S, Li X, Zhang M, Zhang N, Wang R, Chang J. Structural characteristics of small-molecule inhibitors targeting FTO demethylase. Future Med Chem. 2021;13(17):1475–1489.
142.
Bedi RK, Huang D, Eberle SA, Wiedmer L, Sledz P, Caflisch A. Small-molecule inhibitors of METTL3, the major human epitranscriptomic writer. ChemMedChem. 2020;15(9):744–748.
143.
Li J, Gregory RI. Mining for METTL3 inhibitors to suppress cancer. Nat Struct Mol Biol. 2021;28(6):460–462.
144.
Xu Y, Zhang Y, Luo Y, Qiu G, Lu J, He M, Wang Y. Novel insights into the METTL3-METTL14 complex in musculoskeletal diseases. Cell Death Discov. 2023;9(1):170.
145.
Zhang H, Wu S, Chen W, Hu Y, Geng Z, Su J. Bone/cartilage targeted hydrogel: Strategies and applications. Bioact Mater. 2023;23:156–169.
146.
Luo D, Peng S, Li Q, Rao P, Tao G, Wang L, Xiao J. Methyltransferase-like 3 modulates osteogenic differentiation of adipose-derived stem cells in osteoporotic rats. J Gene Med. 2023;25(5): Article e3481.
147.
Chen X, Hua W, Huang X, Chen Y, Zhang J, Li G. Regulatory role of RNA N6-methyladenosine modification in bone biology and osteoporosis. Front Endocrinol. 2019;10:911.
148.
Migliorini F, La Padula G, Torsiello E, Spiezia F, Oliva F, Maffulli N. Strategies for large bone defect reconstruction after trauma, infections or tumour excision: A comprehensive review of the literature. Eur J Med Res. 2021;26(1):118.
149.
Wang W, Yeung K. Bone grafts and biomaterials substitutes for bone defect repair: A review. Bioact Mater. 2017;2(4):224–247.
150.
Chen W, Zhang H, Zhou Q, Zhou F, Zhang Q, Su J. Smart hydrogels for bone reconstruction via modulating the microenvironment. Research. 2023;6:0089.
151.
Jiao X, Sun X, Li W, Chu W, Zhang Y, Li Y, Wang Z, Zhou X, Ma J, Xu C, et al. 3d-printed β-tricalcium phosphate scaffolds promote osteogenic differentiation of bone marrow-deprived mesenchymal stem cells in an N6-methyladenosine-dependent manner. Int J Bioprint. 2022;8(2):544.
152.
Han X, Li G, Yang H, Zhang C, Cao Y, Wang N, Ge L, Fan Z. METTL3 promotes osteo/odontogenic differentiation of stem cells by inhibiting miR-196b-5p maturation. Stem Cells Int. 2023;2023:8992284.
153.
Shi X, Ni H, Wu Y, Guo M, Wang B, Zhang Y, Zhang B, Xu Y. Diagnostic signature, subtype classification, and immune infiltration of key m6A regulators in osteomyelitis patients. Front Genet. 2022;13:1044264.
154.
Hu CY, Jiao Y. A METTL3 inhibitor alleviates the onset of osteomyelitis in a mouse model by targeting MyD88. Jpn J Infect Dis. 2023;76(3):191–196.
155.
Li D, He J, Fang C, Zhang Y, He M, Zhang Z, Hou J, Xu Q. METTL3 regulates osteoclast biological behaviors via iNOS/NO-mediated mitochondrial dysfunction in inflammatory conditions. Int J Mol Sci. 2023;24(2):1403.
156.
Yao Q, Wu X, Tao C, Gong W, Chen M, Qu M, Zhong Y, He T, Chen S, Xiao G. Osteoarthritis: Pathogenic signaling pathways and therapeutic targets. Signal Transduct Target Ther. 2023;8(1):56.
157.
Li X, Li X, Yang J, Du Y, Chen L, Zhao G, Ye T, Zhu Y, Xu X, Deng L, et al. In situ sustained macrophage-targeted nanomicelle-hydrogel microspheres for inhibiting osteoarthritis. Research. 2023;6:0131.
158.
Guo X, Xi L, Yu M, Fan Z, Wang W, Ju A, Liang Z, Zhou G, Ren W. Regeneration of articular cartilage defects: Therapeutic strategies and perspectives. J Tissue Eng. 2023;14:20417314231164765.
159.
Liu Q, Li M, Jiang L, Jiang R, Fu B. METTL3 promotes experimental osteoarthritis development by regulating inflammatory response and apoptosis in chondrocyte. Biochem Biophys Res Commun. 2019;516(1):22–27.
160.
Sang W, Xue S, Jiang Y, Lu H, Zhu L, Wang C, Ma J. METTL3 involves the progression of osteoarthritis probably by affecting ECM degradation and regulating the inflammatory response. Life Sci. 2021;278: Article 119528.
161.
Xie X, Zhang Y, Yu J, Jiang F, Wu C. Significance of m6A regulatory factor in gene expression and immune function of osteoarthritis. Front Physiol. 2022;13: Article 918270.
162.
Zhang H, Li X, Li Y, Yang X, Liao R, Wang H, Yang J. CREB ameliorates osteoarthritis progression through regulating chondrocytes autophagy via the miR-373/METTL3/TFEB axis. Front Cell Dev Biol. 2021;9: Article 778941.
163.
Ren J, Li Y, Wuermanbieke S, Hu S, Huang G. N6-methyladenosine (m6A) methyltransferase METTL3-mediated LINC00680 accelerates osteoarthritis through m6A/SIRT1 manner. Cell Death Discov. 2022;8(1):240.
164.
Shi L, Hu H, Sun P, Li Z, Ji L, Liu S, Zhang J. RPL38 knockdown inhibits the inflammation and apoptosis in chondrocytes through regulating METTL3-mediated SOCS2 m6A modification in osteoarthritis. Inflamm Res. 2022;71(7-8):977–989.
165.
Yao M-D, Jiang Q, Ma Y, Liu C, Zhu C-Y, Sun Y-N, Shan K, Ge H-M, Zhang Q-Y, Zhang H-Y, et al. Role of METTL3-dependent N6-methyladenosine mRNA modification in the promotion of angiogenesis. Mol Ther. 2020;28(10):2191–2202.
166.
Kong Y, Zhang Y, Cai Y, Li D, Yi B, Xu Q. METTL3 mediates osteoblast apoptosis by regulating endoplasmic reticulum stress during LPS-induced inflammation. Cell Signal. 2022;95: Article 110335.
Appendix
Less
Year 2024 volume 7 Issue 4
PDF
228
127
Cite this Article
BibTeX
Article Info
doi: 10.34133/research.0340
  • Receive Date：2023-11-13
  • Online Date：2025-07-24
  • Published：2024-04-25
Article Data
Affiliations
History
  • Received：2023-11-13
  • Accepted：2024-02-21
Funding
China-Japan Friendship Hospital Youth Science and Technology Excellence Project (2022-HX-JC-7)
the Young Taishan Scholars Program of Shandong Province(tsqn201909183)
Natural Science Foundation of China(82302682)
Beijing Natural Science Foundation(7242127)
Natural Science Foundation of Shandong Province (ZR2020QH072)
Jinan Clinical Medical Science and Technology Innovation Program (202328067)
Elite Medical Professionals project of China-Japan Friendship Hospital(ZRJY2021-GG12)
Affiliations
    1Department of Orthopedics, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan 250021, China.
    2School of Mechanical Engineering, Sungkyunkwan University, Suwon 16419, South Korea.
    3Department of Orthopaedic Surgery, Peking University Third Hospital, Peking University, Beijing 100191, China.
    4State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China.
    5Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an 710054, China.
    6 Department of Orthopedics, China-Japan Friendship Hospital, Beijing 100029, China.
    7Department of Orthopaedic Surgery of the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Corresponding:

* Address correspondence to: (F.G.); (W.S.)
References
Share
https://castjournals.cast.org.cn/joweb/research/EN/10.34133/research.0340
Share to
QR

Scan QR to access full text

Cite this article
BibTeX
Citations
表12种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
关闭全屏
  • BibTeX
  • EndNote
  • RefWorks
  • TxT
Links
Articles
Latest Articles
Most Read
Collections
Updates
Events
News
Multimedia
About
About Us
Contact
No. 86 Xueyuan South Road, Haidian District, Beijing
100081
010-62199257
qkjq@cast.org.cn

Copyright © 2025 China Association for Science and Technology. All rights reserved. For all open access content, the relevant licensing terms apply.
Sponsored by the Office of the Leading Group for Cybersecurity and Informatization of CAST, and supported by Science and Technology Review Publishing House