bims-mirbon 2022-01-02 papers

Issue of 2022–01–02
five papers selected by
Japneet Kaur, Mayo Clinic

J Tissue Eng Regen Med. 2021 Dec 27.

LncRNA MALAT1 promotes osteogenic differentiation of BMSCs and inhibits osteoclastic differentiation of Mø in osteoporosis via the miR-124-3p/IGF2BP1/Wnt/β-catenin axis.

Xiangxin Li.

Osteoporosis is defined as a skeletal disorder characterized by impairment in bone strength. The potential application of lncRNAs as therapeutic targets for osteoporosis has been unveiled. This study investigated the regulatory mechanism of lncRNA MALAT1 in the differentiation of bone marrow stem cells (BMSCs) and macrophages (Mø) in osteoporosis. MALAT1 expression in peripheral blood of elderly osteoporosis patients and healthy volunteers was detected. BMSCs and mononuclear Mø were isolated and cultured. Osteogenic differentiation of BMSCs and osteoclastic differentiation of Mø were induced. BMSCs and Mø were transfected with si-MALAT1, miR-124-3p mimics, miR-124-3p inhibitor, or pcDNA IGF2BP1, followed by detection of cell differentiation. The target microRNAs (miRs) and downstream genes and signaling pathways of MALAT1 were examined. The ovariectomy-induced mouse model of osteoporosis was established, and the mice were injected with pcDNA-MALAT1. MALAT1 was downregulated in osteoporosis patients, increased in BMSCs after osteogenic differentiation, and diminished in Mø after osteoclastic differentiation. Downregulation of MALAT1 repressed osteogenic differentiation of BMSCs and facilitated osteoclastic differentiation of Mø. MALAT1 upregulated IGF2BP1 expression by competitively binding to miR-124-3p. miR-124-3p silencing reversed the effect of si-MALAT1 on BMSCs and Mø differentiation, and IGF2BP1 upregulation averted the effect of overexpressed-miR-124-3p by activating the Wnt/β-catenin pathway. Upregulation of MALAT1 activated the Wnt/β-catenin pathway and attenuated bone injury in mice. In conclusion, lncRNA MALAT1 promoted the osteogenic differentiation of BMSCs and inhibited osteoclastic differentiation of Mø in osteoporosis via the miR-124-3p/IGF2BP1/Wnt/β-catenin axis. This article is protected by copyright. All rights reserved.

Keywords: Competitive endogenous RNA; IGF2BP1; LncRNA MALAT1; Osteoclastic differentiation; Osteogenic differentiation; Osteoporosis; Wnt/β-catenin pathway; miR-124-3p

DOI: https://doi.org/10.1002/term.3279

Exp Ther Med. 2022 Feb;23(2): 127

miR-27b attenuates dexamethasone-inhibited proliferation and osteoblastic differentiation in MC3T3-E1 cells by targeting PPARγ2.

Huicheng Lv, Tieyi Yang, Aimin He, Mingbo Wang, Haisheng Jia, Min Ma, Siqin Li.

Osteoporosis is a metabolic bone illness characterized by low bone density and a high risk of fracture. It is estimated that there are >60 million individuals in China suffering from this disease, which highlights an urgent requirement for the development of novel and safe drugs for the long-term treatment of osteoporosis. MicroRNAs (miRNAs/miRs) have previously been identified as critical regulators in the progression of osteoporosis. As an intronic miRNA, miR-27b enhances the osteoblastic differentiation of stem cells from the bone marrow and the maxillary sinus membrane. However, the mechanism underlying miR-27b in osteoporosis remains to be elucidated. In the present study, MC3T3-E1 pre-osteoblasts were treated with dexamethasone (DEX) to establish an in vitro model of osteoporosis. The results of the present study demonstrated that DEX treatment markedly inhibited the viability of MC3T3-E1 cells, and downregulated the expression level of miR-27b. The results of reverse transcription-quantitative PCR, western blotting and dual-luciferase assays revealed that miR-27b directly regulated and suppressed the expression of peroxisome proliferator-activated receptor γ2 (PPARγ2) in MC3T3-E1 cells. Furthermore, overexpression of miR-27b by transfection of cells with miR-27b mimic attenuated DEX-mediated inhibition of cell viability, alkaline phosphatase (ALP) activity and the expression levels of bone morphogenetic protein-2 (BMP2), runt-related protein 2 (Runx2) and osteocalcin (OCN). The results of the present study indicated that miR-27b alleviated DEX-inhibited proliferation and osteoblastic differentiation. Moreover, miR-27b knockdown repressed MC3T3-E1 cell viability, ALP activity and protein levels of BMP2, Runx2 and OCN. However, these effects were abrogated by small interfering RNA-mediated PPARγ2 silencing. In conclusion, the results of the present study demonstrated that miR-27b attenuated DEX-inhibited proliferation and osteoblastic differentiation in MC3T3-E1 pre-osteoblasts by targeting PPARγ2.

Keywords: PPARγ2; miR-27b; osteoblastic differentiation; proliferation

DOI: https://doi.org/10.3892/etm.2021.11050

Front Immunol. 2021 ;12 781185

Indoleamine 2, 3 Dioxygenase 1 Impairs Chondrogenic Differentiation of Mesenchymal Stem Cells in the Joint of Osteoarthritis Mice Model.

Murad Alahdal, Rongxiang Huang, Li Duan, Deng Zhiqin, Ouyang Hongwei, Wencui Li, Daping Wang.

Osteoarthritis (OA) is a serious joint inflammation that leads to cartilage degeneration and joint dysfunction. Mesenchymal stem cells (MSCs) are used as a cell-based therapy that showed promising results in promoting cartilage repair. However, recent studies and clinical trials explored unsatisfied outcomes because of slow chondrogenic differentiation and increased calcification without clear reasons. Here, we report that the overexpression of indoleamine 2,3 dioxygenase 1 (IDO1) in the synovial fluid of OA patients impairs chondrogenic differentiation of MSCs in the joint of the OA mice model. The effect of MSCs mixed with IDO1 inhibitor on the cartilage regeneration was tested compared to MSCs mixed with IDO1 in the OA animal model. Further, the mechanism exploring the effect of IDO1 on chondrogenic differentiation was investigated. Subsequently, miRNA transcriptome sequencing was performed for MSCs cocultured with IDO1, and then TargetScan was used to verify the target of miR-122-5p in the SF-MSCs. Interestingly, we found that MSCs mixed with IDO1 inhibitor showed a significant performance to promote cartilage regeneration in the OA animal model, while MSCs mixed with IDO1 failed to stimulate cartilage regeneration. Importantly, the overexpression of IDO1 showed significant inhibition to Sox9 and Collagen type II (COL2A1) through activating the expression of β-catenin, since inhibiting of IDO1 significantly promoted chondrogenic signaling of MSCs (Sox9, COL2A1, Aggrecan). Further, miRNA transcriptome sequencing of SF-MSCs that treated with IDO1 showed significant downregulation of miR-122-5p which perfectly targets Wnt1. The expression of Wnt1 was noticed high when IDO1 was overexpressed. In summary, our results suggest that IDO1 overexpression in the synovial fluid of OA patients impairs chondrogenic differentiation of MSCs and cartilage regeneration through downregulation of miR-122-5p that activates the Wnt1/β-catenin pathway.

Keywords: IDO1 inhibitor; MSCs; cartilage regeneration; miR-122-5p; osteoarthritis

DOI: https://doi.org/10.3389/fimmu.2021.781185

Nutr Metab Cardiovasc Dis. 2021 Nov 03. pii: S0939-4753(21)00515-9. [Epub ahead of print]

The BMSC-derived exosomal lncRNA Mir9-3hg suppresses cardiomyocyte ferroptosis in ischemia-reperfusion mice via the Pum2/PRDX6 axis.

Jian-Kai Zhang, Zhi Zhang, Zi-Ao Guo, Yuan Fu, Xiao-Jia Chen, Wei-Jie Chen, Hong-Fu Wu, Xiao-Jun Cui.

BACKGROUND AND AIMS: The exosomal long noncoding RNAs (lncRNAs) have been reported to have cardioprotective effects on ischemia-reperfusion (I/R) injury by hindering ferroptosis, but the role of lncRNA Mir9-3 host gene (Mir9-3hg) in cardiac I/R injury remains unclear.
METHODS AND RESULTS: Exosomes were extracted from mouse bone marrow mesenchymal stem cells (BMSCs) and identified by detecting the exosome specific marker levels, and the results showed that Mir9-3hg was highly expressed in BMSCs-Exo. Hypoxia/reoxygenation (H/R)-treated HL-1 mouse cardiomyocytes were incubated with exosomes extracted from BMSCs transfected with Mir9-3hg siRNA. BMSCs-Exo incubation observably facilitated cell proliferation, increased glutathione (GSH) content, and reduced iron ion concentration, reactive oxygen species (ROS) level and ferroptosis marker protein levels in H/R-treated cells, while interfering Mir9-3hg reversed these effects. RNA binding protein immunoprecipitation assay was found that Mir9-3hg bound with pumilio RNA binding family member 2 (Pum2) protein and downregulated Pum2 expression. Silence of Pum2 reversed the effects of Mir9-3hg inhibition on cell functions. Chromatin immunoprecipitation assay was revealed that Pum2 bound with peroxiredoxin 6 (PRDX6) promoter and restrained PRDX6 expression. Silence of PRDX6 reversed the improved effects of Pum2 downregulation on cell functions. Additionally, BMSCs-Exo treatment ameliorated cardiac function in I/R-treated mice by inhibiting cardiomyocyte ferroptosis.
CONCLUSIONS: BMSCs-Exo treatment attenuates I/R-induced cardiac injury by inhibiting cardiomyocyte ferroptosis through modulating the Pum2/PRDX6 axis, thereby ameliorating cardiac function.

Keywords: BMSCs-Exo; Ferroptosis; Ischemia-reperfusion; PRDX6; Pum2; lncRNA Mir9-3hg

DOI: https://doi.org/10.1016/j.numecd.2021.10.017

Bioengineered. 2021 Dec;12(1): 1189-1201

Long non-coding RNA SND1-IT1 accelerates cell proliferation, invasion and migration via regulating miR-132-3p/SMAD2 axis in retinoblastoma.

Dong-Fang Yin, Xue-Jun Zhou, Na Li, Hui-Jie Liu, Hu Yuan.

Long noncoding RNAs (lncRNAs) have been identified as prognostic biomarkers and functional regulators in human tumors. In our study, we aim to investigate the roles of lncRNA SND1-IT1 (SND1-IT1) in retinoblastoma (RB). We observed that SND1-IT1 was highly expressed in both RB specimens and cells, and associated with poorer prognosis of RB patients. Functional investigation revealed that downregulation of SND1-IT1 suppressed RB cell proliferation, migration and invasion in vitro and restrained RB tumorigenesis in vivo. MiR-132-3p was predicted to interact with SND1-IT1. RT-qPCR and dual-luciferase reporter assays verified the regulation of miR-132-3p by SND1-IT1 in RB cells. In addition, SND1-IT1 enhanced the expression of SMAD2 by sponging miR-132-3p. Rescue experiments revealed that knockdown of miR-132-3p reversed the inhibiting effects of miR-132-3p knockdown on RB cells. Overall, SND1-IT1 can promote the progression of RB cells through miR-132-3p/SMAD2 axis, suggesting that l SND1-IT1 might be a novel biomarker and potential target for RB.

Keywords: LncRNA SND1-IT1; SMAD2; biomarker; metastasis; miR-132-3p; retinoblastoma

DOI: https://doi.org/10.1080/21655979.2021.1909962