bims-mirbon Biomed News
on MicroRNAs in bone
Issue of 2021–12–05
eight papers selected by
Japneet Kaur, Mayo Clinic
  1. CircSmg5 stimulates the osteogenic differentiation of bone marrow mesenchymal stem cells by targeting the miR-194-5p/Fzd6 axis and beta-catenin signaling.
  2. microRNA-136-5p from bone marrow mesenchymal stem cell-derived exosomes facilitates fracture healing by targeting LRP4 to activate the Wnt/β-catenin pathway.
  3. MiR-144-3p Aggravated Cartilage Injury in Rheumatoid Arthritis by Regulating BMP2/PI3K/Akt Axis.
  4. Mesenchymal Stem Cell-Originated Exosomal Circular RNA circFBXW7 Attenuates Cell Proliferation, Migration and Inflammation of Fibroblast-Like Synoviocytes by Targeting miR-216a-3p/HDAC4 in Rheumatoid Arthritis.
  5. MiR-125a-3p inhibits cell proliferation and inflammation responses in fibroblast-like synovial cells in rheumatoid arthritis by mediating the Wnt/β-catenin and NF-κB pathways via targeting MAST3.
  6. miR-21 regulates osteogenic and adipogenic differentiation of BMSCs by targeting PTEN.
  7. Identification of transcription factors and construction of a novel miRNA regulatory network in primary osteoarthritis by integrated analysis.
  8. Identification of miRNA Regulatory Networks and Candidate Markers for Fracture Healing in Mice.
  1. Environ Toxicol. 2021 Dec 01.
    CircSmg5 stimulates the osteogenic differentiation of bone marrow mesenchymal stem cells by targeting the miR-194-5p/Fzd6 axis and beta-catenin signaling.
    Yue Lu, Ya Ke Liu, Fu Yin Wan, Song Shi, Ran Tao.
       BACKGROUND: Osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is closely associated with bone diseases. Circular RNAs are reported to be involved in BMSC differentiation. CircSmg5 (circ_0001145) has been identified to be downregulated in an osteoporosis mouse model. In this study, we aimed to explore the function and regulatory mechanism of circSmg5 in BMSC osteogenic differentiation.
    METHODS: The Alizarin Red staining and alkaline phosphatase staining assays were performed to explore the osteogenic differentiation of BMSCs. The interaction between circ_0001145, miR-194-5p, and frizzled class receptor 6 (Fzd6) was analyzed by luciferase reporter assay. The nuclear translocation of β-catenin was assessed using immunofluorescence staining.
    RESULTS: CircSmg5 is in stable circular structure. CircSmg5 expression was elevated in the process of BMSC osteogenic differentiation. CircSmg5 overexpression promoted the osteogenic differentiation of BMSCs. CircSmg5 bound with miR-194-5p, whose expression was decreased in the osteogenic differentiation of BMSCs. MiR-194-5p directly targeted the 3'UTR of Fzd6. The mRNA and protein levels of Fzd6 were positively modulated by circSmg5 and negatively regulated by miR-194-5p in BMSCs.
    CONCLUSION: CircSmg5 was demonstrated to promote the BMSC osteogenic differentiation by targeting the miR-194-5p/Fzd6 axis to activate the Wnt/β-catenin signaling.
    Keywords:  BMSC osteogenic differentiation; Fzd6; circSmg5; miR-194-5p
    DOI:  https://doi.org/10.1002/tox.23425
  2. Bone Joint Res. 2021 Dec;10(12): 744-758
    microRNA-136-5p from bone marrow mesenchymal stem cell-derived exosomes facilitates fracture healing by targeting LRP4 to activate the Wnt/β-catenin pathway.
    Haichi Yu, Jun Zhang, Xiaoning Liu, Yingzhi Li.
       AIMS: Exosomes derived from bone marrow mesenchymal stem cells (BMSCs) have been reported to be a promising cellular therapeutic approach for various human diseases. The current study aimed to investigate the mechanism of BMSC-derived exosomes carrying microRNA (miR)-136-5p in fracture healing.
    METHODS: A mouse fracture model was initially established by surgical means. Exosomes were isolated from BMSCs from mice. The endocytosis of the mouse osteoblast MC3T3-E1 cell line was analyzed. CCK-8 and disodium phenyl phosphate microplate methods were employed to detect cell proliferation and alkaline phosphatase (ALP) activity, respectively. The binding of miR-136-5p to low-density lipoprotein receptor related protein 4 (LRP4) was analyzed by dual luciferase reporter gene assay. HE staining, tartrate-resistant acid phosphatase (TRAP) staining, and immunohistochemistry were performed to evaluate the healing of the bone tissue ends, the positive number of osteoclasts, and the positive expression of β-catenin protein, respectively.
    RESULTS: miR-136-5p promoted fracture healing and osteoblast proliferation and differentiation. BMSC-derived exosomes exhibited an enriched miR-136-5p level, and were internalized by MC3T3-E1 cells. LRP4 was identified as a downstream target gene of miR-136-5p. Moreover, miR-136-5p or exosomes isolated from BMSCs (BMSC-Exos) containing miR-136-5p activated the Wnt/β-catenin pathway through the inhibition of LRP4 expression. Furthermore, BMSC-derived exosomes carrying miR-136-5p promoted osteoblast proliferation and differentiation, thereby promoting fracture healing.
    CONCLUSION: BMSC-derived exosomes carrying miR-136-5p inhibited LRP4 and activated the Wnt/β-catenin pathway, thus facilitating fracture healing. Cite this article: Bone Joint Res 2021;10(12):744-758.
    Keywords:  Bone marrow mesenchymal stem cells; Exosomes; miR-136-5p
    DOI:  https://doi.org/10.1302/2046-3758.1012.BJR-2020-0275.R2
  3. Mod Rheumatol. 2021 Nov 30. pii: roab105. [Epub ahead of print]
    MiR-144-3p Aggravated Cartilage Injury in Rheumatoid Arthritis by Regulating BMP2/PI3K/Akt Axis.
    Mei-Li Mo, Jin-Mei Jiang, Xiao-Ping Long, Li-Hu Xie.
       OBJECTIVES: Present study aimed to illustrate the role of miR-144-3p in RA.
    METHODS: N1511 chondrocytes were stimulated by IL-1β to mimic RA injury model in vitro. Rats were subjected to injection of type II collagen to establish an in vivo RA model and the arthritis index score was calculated. Cell viability was determined by CCK-8. The expression of cartilage extracellular matrix proteins (Collagen II and Aggrecan) and matrix metalloproteinases protein (MMP-13) were determined by qRT-PCR and western blots. Cell apoptosis was measured by Flow cytometry. ELISA was applied to test the secretion of pro-inflammatory cytokines (IL-1β and TNF-α). Tissue injury and apoptosis were detected by HE staining and TUNEL staining. Interaction of miR-144-3p and BMP2 was verified by dual luciferase assay.
    RESULTS: MiR-144-3p was dramatically increased in IL-1β induced N1511 cells. MiR-144-3p depletion elevated cell viability, suppressed apoptosis, pro-inflammatory cytokine releasing, and extracellular matrix loss in IL-1β induced N1511 cells. Moreover, miR-144-3p targeted BMP2 to modulate its expression negatively. Activation of PI3K/Akt signaling compromised inhibition of BMP2 induced aggravated N1511 cell injury with IL-1β stimulation. Inhibition of miR-144-3p alleviated cartilage injury and inflammatory in RA rats.
    CONCLUSION: Collectively, miR-144-3p could aggravate chondrocytes injury inflammatory response in RA via BMP2/PI3K/Akt axis.
    Keywords:  BMP2; PI3K/Akt; chondrocytes injury; miR-144-3p; rheumatoid arthritis
    DOI:  https://doi.org/10.1093/mr/roab105
  4. J Inflamm Res. 2021 ;14 6157-6171
    Mesenchymal Stem Cell-Originated Exosomal Circular RNA circFBXW7 Attenuates Cell Proliferation, Migration and Inflammation of Fibroblast-Like Synoviocytes by Targeting miR-216a-3p/HDAC4 in Rheumatoid Arthritis.
    Lihua Chang, Liang Kan.
       Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease of articular joint damage and elevated synovial hyperplasia. Abnormal proliferation, invasion inflammatory response of rheumatoid fibroblast-like synoviocytes (RA-FLS) play a critical role in RA progression. Mesenchymal stem cell (MSC)-derived exosomal circular RNAs are promising therapeutic manner for disease treatment. This work aimed to decipher the role of exosomal circFBXW7 in RA.
    Methods: The expression of circFBXW7, miR-216a-3p, and HDAC4 were detected in clinical RA samples. The RA rat model was established. Isolation and identification of exosomes from MSCs was conducted. The effects of exosomal circFBXW7 on RA was evaluated by qPCR, CCK-8, transwell assays, flow cytometry, Western blotting, ELISA, and immunohistochemical assay. Interaction between miR-216a-3p and circFBXW7 or HDAC4 was determined by luciferase reporter gene assay and RNA pulldown.
    Results: Exosomal circFBXW7 treatment suppressed proliferation, migration and inflammatory response of RA-FLSs and damage of RA model. CircFBXW7 could directly sponge miR-216a-3p to upregulate the expression of HDAC4. Inhibition of HDAC4 or upregulation of miR-216a-3p abolished the therapeutic function of exosomal circFBXW7. Our data demonstrated that circFBXW7 and HDAC4 were decreased, and miR-216a-3p was elevated in clinical RA sample compared with healthy samples.
    Conclusion: We concluded that MSC-derived exosomal circFBXW7 suppressed proliferation, migration and inflammatory response of RA-FLSs and damage of RA rats via sponging miR-216a-3p and release the activation of HDAC4. These findings may provide a novel therapeutic target for RA.
    Keywords:  HDAC4; circFBXW7; fibroblast-like synoviocytes; mesenchymal stem cell; miR-216a-3p; rheumatoid arthritis
    DOI:  https://doi.org/10.2147/JIR.S336099
  5. J Musculoskelet Neuronal Interact. 2021 Dec 01. 21(4): 560-567
    MiR-125a-3p inhibits cell proliferation and inflammation responses in fibroblast-like synovial cells in rheumatoid arthritis by mediating the Wnt/β-catenin and NF-κB pathways via targeting MAST3.
    Yingxue Wang, Zhe Yin, Ni Zhang, Huishu Song, Qiuting Zhang, Xuexi Hao, Zhilun Wang.
       OBJECTIVES: To explore the role and mechanism of miR-125a-3p in rheumatoid arthritis (RA) progression.
    METHODS: The RA-tissues and fibroblast-like synovial cells in rheumatoid arthritis (RA-FLS) were used in this study. qRT-PCR, western blot and ELISA assay were performed to detect the expression levels of IL-6, IL-β and ΤΝF-α. Dual-luciferase reporter gene assay was used to observe the binding effect of miR-125a-3p and MAST3, and CCK-8 was used to observe the effect of miR-125a-3p on the proliferation of RA-FLS.
    RESULTS: miR-125a-3p was significantly downregulated in the RA-tissues and RA-FLS, and miR-125a-3p could inhibit the proliferation and reduce the inflammation response of RA-FLS. Besides, MAST3 was found as a target of miR-125a-3p, and increased MAST3 could reverse the effects of miR-125a-3p on RA-FLS including decreased proliferation, reduced inflammation level and the inactivation of Wnt/β-catenin and NF-κB pathways.
    CONCLUSIONS: This study suggests that miR-125a-3p could inactivate the Wnt/β-catenin and NF-κB pathways to reduce the proliferation and inflammation response of RA-FLS via targeting MAST3.
    Keywords:  MAST3; NF-κB; Rheumatoid Arthritis; Wnt/β-catenin; miR-125a-3p
  6. J Musculoskelet Neuronal Interact. 2021 Dec 01. 21(4): 568-576
    miR-21 regulates osteogenic and adipogenic differentiation of BMSCs by targeting PTEN.
    Yongtao Zhou, Hongwang Qiao, Lili Liu, Ping Dong, Fangxu Zhu, Jiawen Zhang, Liping Liu, Li Liu.
       OBJECTIVE: To explore the effects and mechanism of miR-21 on the osteogenic/adipogenic differentiation of mouse BMSCs.
    METHODS: The bilateral ovaries of C57BL/6J mice (n=24) were removed to construct an osteoporosis model. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-21, osteogenic/adipogenic genes, and PTEN. ALP and ARS and ORO staining were used to detect the formation of calcium nodules and lipid droplets in BMSCs. Western blot was used to detect the expression of PTEN.
    RESULTS: miR-21 was significantly down-regulated in osteoporotic mice. The expression of miR-21 was significantly up-regulated after the osteogenic induction of BMSCs, and the expression of miR-21 was significantly down-regulated after the adipogenic induction. Overexpression of miR-21 significantly promoted the osteogenic differentiation of BMSCs and inhibits the adipogenic differentiation of BMSCs.
    CONCLUSION: MiR-21 can promote osteogenic differentiation of BMSCs and inhibit their adipogenic differentiation by negatively regulating PTEN.
    Keywords:  Adipose differentiation; BMSCs; Osteogenic Differentiation; Osteoporosis; miRNA
  7. BMC Musculoskelet Disord. 2021 Dec 02. 22(1): 1008
    Identification of transcription factors and construction of a novel miRNA regulatory network in primary osteoarthritis by integrated analysis.
    Ying Jiang, Yi Shen, Liyan Ding, Shengli Xia, Liying Jiang.
       BACKGROUNDS: As osteoarthritis (OA) disease-modifying therapies are not available, novel therapeutic targets need to be discovered and prioritized. Here, we aim to identify miRNA signatures in patients to fully elucidate regulatory mechanism of OA pathogenesis and advance in basic understanding of the genetic etiology of OA.
    METHODS: Six participants (3 OA and 3 controls) were recruited and serum samples were assayed through RNA sequencing (RNA-seq). And, RNA-seq dataset was analysed to identify genes, pathways and regulatory networks dysregulated in OA. The overlapped differentially expressed microRNAs (DEMs) were further screened in combination with the microarray dataset GSE143514. The expression levels of candidate miRNAs were further validated by quantitative real-time PCR (qRT-PCR) based on the GEO dataset (GSE114007).
    RESULTS: Serum samples were sequenced interrogating 382 miRNAs. After screening of independent samples and GEO database, the two comparison datasets shared 19 overlapped candidate micRNAs. Of these, 9 up-regulated DEMs and 10 down-regulated DEMs were detected, respectively. There were 236 target genes for up-regulated DEMs and 400 target genes for those down-regulated DEMs. For up-regulated DEMs, the top 10 hub genes were KRAS, NRAS, CDC42, GDNF, SOS1, PIK3R3, GSK3B, IRS2, GNG12, and PRKCA; for down-regulated DEMs, the top 10 hub genes were NR3C1, PPARGC1A, SUMO1, MEF2C, FOXO3, PPP1CB, MAP2K1, RARA, RHOC, CDC23, and CREB3L2. Mir-584-5p-KRAS, mir-183-5p-NRAS, mir-4435-PIK3R3, and mir-4435-SOS1 were identified as four potential regulatory pathways by integrated analysis.
    CONCLUSIONS: We have integrated differential expression data to reveal putative genes and detected four potential miRNA-target gene pathways through bioinformatics analysis that represent new mediators of abnormal gene expression and promising therapeutic targets in OA.
    Keywords:  Bioinformatics analysis; Circulating microRNAs; Osteoarthritis; RNA sequencing
    DOI:  https://doi.org/10.1186/s12891-021-04894-2
  8. Comput Math Methods Med. 2021 ;2021 2866475
    Identification of miRNA Regulatory Networks and Candidate Markers for Fracture Healing in Mice.
    Xianglu Li, Zhaohua Zhong, Enguang Ma, Xiaowei Wu.
       Background: It is important to improve the understanding of the fracture healing process at the molecular levels, then to discover potential miRNA regulatory mechanisms and candidate markers.
    Methods: Expression profiles of mRNA and miRNA were obtained from the Gene Expression Omnibus database. We performed differential analysis, enrichment analysis, protein-protein interaction (PPI) network analysis. The miRNA-mRNA network analysis was also performed.
    Results: We identified 499 differentially expressed mRNAs (DEmRs) that were upregulated and 534 downregulated DEmRs during fracture healing. They were mainly enriched in collagen fibril organization and immune response. Using the PPI network, we screened 10 hub genes that were upregulated and 10 hub genes downregulated with the largest connectivity. We further constructed the miRNA regulatory network for hub genes and identified 13 differentially expressed miRNAs (DEmiRs) regulators. Cd19 and Col6a1 were identified as key candidate mRNAs with the largest fold change, and their DEmiR regulators were key candidate regulators.
    Conclusion: Cd19 and Col6a1 might serve as candidate markers for fracture healing in subsequent studies. Their expression is regulated by miRNAs and is involved in collagen fibril organization and immune responses.
    DOI:  https://doi.org/10.1155/2021/2866475
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