Tumor-derived extracellular vesicles inhibit osteogenesis and exacerbate myeloma bone disease

Zhang, Liming; Lei, Qian; Wang, Hongxiang; Xu, Cuiwei; Liu, Teng; Kong, Fancong; Yang, Cui; Yan, Gen; Sun, Li; Zhao, Aiqi; Chen, Wenlan; Hu, Yu; Xie, Hui; Cao, Yulin; Fu, Fenfen; Yuan, Guolin; Chen, Zhichao; Guo, An‐Yuan; Li, Qiubai

doi:10.7150/thno.27550

Cited by 51 publications

(61 citation statements)

References 56 publications

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“…Multiple lines of evidence define the involvement of EVs in MM progression as they can act on several cellular targets and at different levels of disease progression [12][13][14][15][16][17][18][19]. In particular, recent findings have highlighted the role of EVs as inducers of MM-osteolytic bone disease [21][22][23][24][25][26][27].…”

Section: Discussionmentioning

confidence: 99%

“…EVs released by MM cells have been recently correlated to the MM bone disease by directly activating osteoclast functions and, at the same time, by inhibiting the osteogenic differentiation of hMSCs [21][22][23][24][25]27]. In our previous study, we demonstrated that MM EVs inhibit the osteoblastic differentiation of hTERT-MSCs [21]; here we tried to shed light on the mechanism underlying these effects.…”

Section: Evs Are Internalized By Hmscs and Inhibit Their Osteogenimentioning

confidence: 95%

“…Recent studies have shown that MM cell-derived EVs play a relevant functional role in activating osteoclast differentiation [21][22][23] and that the presence of the EGFR ligand amphiregulin is partially responsible for OC activation [21]. Interestingly, increasing evidence reported that MM EVs are also effective in inhibiting osteogenesis, in particular by blocking the osteoblastic differentiation of mesenchymal cells [21,[23][24][25][26][27]. In particular, the decrease in ALPL levels, both at the transcript and protein levels, was largely correlated with MM-EVs mediated osteogenic inhibition [21,23,24].…”

Section: Introductionmentioning

confidence: 99%

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Extracellular Vesicle microRNAs Contribute to the Osteogenic Inhibition of Mesenchymal Stem Cells in Multiple Myeloma

Raimondo

Urzì

Conigliaro

et al. 2020

Cancers

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Osteolytic bone disease is the major complication associated with the progression of multiple myeloma (MM). Recently, extracellular vesicles (EVs) have emerged as mediators of MM-associated bone disease by inhibiting the osteogenic differentiation of human mesenchymal stem cells (hMSCs). Here, we investigated a correlation between the EV-mediated osteogenic inhibition and MM vesicle content, focusing on miRNAs. By the use of a MicroRNA Card, we identified a pool of miRNAs, highly expressed in EVs, from MM cell line (MM1.S EVs), expression of which was confirmed in EVs from bone marrow (BM) plasma of patients affected by smoldering myeloma (SMM) and MM. Notably,we found that miR-129-5p, which targets different osteoblast (OBs) differentiation markers, is enriched in MM-EVs compared to SMM-EVs, thus suggesting a selective packaging correlated with pathological grade. We found that miR-129-5p can be transported to hMSCs by MM-EVs and, by the use of miRNA mimics, we investigated its role in recipient cells. Our data demonstrated that the increase of miR-129-5p levels in hMSCs under osteoblastic differentiation stimuli inhibited the expression of the transcription factor Sp1, previously described as a positive modulator of osteoblastic differentiation, and of its target the Alkaline phosphatase (ALPL), thus identifying miR-129-5p among the players of vesicle-mediated bone disease.

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Section: Discussionmentioning

confidence: 99%

Section: Evs Are Internalized By Hmscs and Inhibit Their Osteogenimentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Extracellular Vesicle microRNAs Contribute to the Osteogenic Inhibition of Mesenchymal Stem Cells in Multiple Myeloma

Raimondo

Urzì

Conigliaro

et al. 2020

Cancers

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“…Piwi-interacting RNAs (piRNAs) are 21 to 35 nucleotides segments of RNA that can orginate from lncRNAs and are active during development [27]. These are also found in extracellular vesicles (EV), including those from multiple meloma bone disease that are capable of inhibiting osteogenesis [28].…”

Section: Osteogenesis: Cell Proliferation and Differentiationmentioning

confidence: 99%

Bio-activating ultrafine grain titanium: RNA sequencing reveals enhanced mechano-activation of osteoconduction on nanostructured substrates

et al. 2020

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Titanium is essentially absent from biological systems yet reliably integrates into bone. To achieve osseointegration, titanium must activate biological processes without entering cells, defining it as a bio-activating material. Nanostructuring bulk titanium reduces grain size, increases strength, and improves other quantifiable physical properties, including cytocompatibility. The biological processes activated by increasing grain boundary availability were detected with total RNA-sequencing in mouse pre-osteoblasts grown for 72 hours on nanometrically smooth substrates of either coarse grain or nanostructured ultrafine grain titanium. The average grain boundary length under cells on the conventional coarse grain substrates is 273.0 μm, compared to 70,881.5 μm for cells adhered to the nanostructured ultrafine grain substrates; a 260-fold difference. Cells on both substrates exhibit similar expression profiles for genes whose products are critical for mechanosensation and transduction of cues that trigger osteoconduction. Biological process Gene Ontology term enrichment analysis of differentially expressed genes reveals that cell cycle, chromatin modification, telomere maintenance, and RNA metabolism processes are upregulated on ultrafine grain titanium. Processes related to immune response, including apoptosis, are downregulated. Tumor-suppressor genes are upregulated while tumor-promoting genes are downregulated. Upregulation of genes involved in chromatin remodeling and downregulation of genes under the control of the peripheral circadian clock implicate both processes in the transduction of mechanosensory information. Non-coding RNAs may also play a role in the response. Merging transcriptomics with well-established mechanobiology principles generates a unified model to explain the bio-activating properties of titanium. The modulation of processes is accomplished through chromatin remodeling in which the nucleus responds like a rheostat to grain boundary concentration.

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“…Then, when the cultured cell fusion degree reached between 60% and 70%, the cells were carefully sucked out in order the complete the culture medium, and 2 ml of osteogenic differentiation culture medium were added. The induced differentiation was stained on the 21st day [19,20] .…”

Section: Msc Differentiationsmentioning

confidence: 99%

The Effects of METTL3-Mediated Regulations of the Adipogenic Differentiations of Bone Marrow MSCs Targeting PI3K/AKT Pathways on the Chemo-Resistance of AML

Pan¹,

Wang²,

Hou³

et al. 2020

Preprint

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Background: The adipogenic differentiations of bone marrow mesenchymal stem cells (MSCs) result in the promotion of the chemo-resistance of AML cells. When compared with bone marrow MSCs from healthy donors (HD-MSCs), it has been observed that the MSCs from AML (AML-MSCs) displayed enhanced adipogenic differentiation abilities. However, the underlying mechanism remains elusive. METTL3-mediated modifications of m6A mRNA play key roles in the regulation of stem cell differentiation. Unfortunately, there has been no research to date which has reported the fact that the increases of adipogenic differentiation of AML-MSCs are regulated by the m6A. The goal of this study was to investigate the critical role of METTL3 in the adipogenesis of AML-MSCs for promoting the chemo-resistance of AML.Methods: This study detected the m6A levels of the MSCs total RNA, and then investigated METTL3 functions in the adipogenic differentiations of MSCs using knockdown and overexpression experimental methods. The effects of the adipogenic differentiations of HD-MSCs/AML-MSCs on the chemo-resistance to AML were also examined. In addition, the gene transcriptome and m6A epigenetic changes of AML-MSCs from four AML patients, and the HD-MSCs from three healthy donors, were analyzed in this study. The differentially expressed genes and pathways were successfully identified, and clinical specimens were used to adjust gene expressions in order to determine their effects on the adipogenic differentiations of MSC.Results: The results demonstrated that METTL3 could significantly inhibit the adipogenic differentiations of MSCs. It was found that when compared with the HD-MSCs, the expressions of the PI3K/AKT signaling pathways in the AML-MSCs were significantly increased. Meanwhile, the levels of m6A were significantly decreased. Therefore, it was indicated that by blocking the PI3K/AKT signaling pathways with AKT inhibitors, the adipogenic differentiations of the MSCs could be significantly inhibited. Moreover, the increased adipogenic differentiations induced by the METTL3 could significantly increase the chemo-resistance of the AML.Conclusions: It was found that the METTL3 had enhanced the modification levels of m6A in the PI3K/AKT signaling pathways, and then reduced its expression. Subsequently, the adipogenic differentiations were inhibited. Then, the bone marrow microenvironments, as well as chemo-resistance of the AML, were successfully changed.

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Tumor-derived extracellular vesicles inhibit osteogenesis and exacerbate myeloma bone disease

Cited by 51 publications

References 56 publications

Extracellular Vesicle microRNAs Contribute to the Osteogenic Inhibition of Mesenchymal Stem Cells in Multiple Myeloma

Extracellular Vesicle microRNAs Contribute to the Osteogenic Inhibition of Mesenchymal Stem Cells in Multiple Myeloma

Bio-activating ultrafine grain titanium: RNA sequencing reveals enhanced mechano-activation of osteoconduction on nanostructured substrates

The Effects of METTL3-Mediated Regulations of the Adipogenic Differentiations of Bone Marrow MSCs Targeting PI3K/AKT Pathways on the Chemo-Resistance of AML

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