MiR-101 Targets the EZH2/Wnt/β-Catenin the Pathway to Promote the Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells

Wang, Hongrui; Meng, Yake; Cui, Quanjun; Qin, Fujun; Yang, Haisong; Chen, Yu; Cheng, Yajun; Shi, Jiangang; Guo, Yongfei

doi:10.1038/srep36988

Cited by 50 publications

(41 citation statements)

References 44 publications

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“…Thus, EZH2 inhibitors may have bone anabolic activity and anti‐bone resorptive activity. Furthermore, enhanced osteogenic differentiation of human MSCs using EZH2 inhibitors or molecular pathways drugs that indirectly impinge on EZH2 may have practical implications for bone tissue engineering.…”

Section: The Basics Of Epigeneticsmentioning

confidence: 99%

Epigenetics as a New Frontier in Orthopedic Regenerative Medicine and Oncology

Wijnen

Westendorf

2019

Journal Orthopaedic Research

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Skeletal regenerative medicine aims to repair or regenerate skeletal tissues using pharmacotherapies, cell-based treatments, and/or surgical interventions. The field is guided by biological principles active during development, wound healing, aging, and carcinogenesis. Skeletal development and tissue maintenance in adults represent highly intricate biological processes that require continuous adjustments in the expression of cell type-specific genes that generate, remodel, and repair the skeletal extracellular matrix. Errors in these processes can facilitate musculoskeletal disease including cancers or injury. The fundamental molecular mechanisms by which cell type-specific patterns in gene expression are established and retained during successive mitotic divisions require epigenetic control, which we review here. We focus on epigenetic regulatory proteins that control the mammalian epigenome at the level of chromatin with emphasis on proteins that are amenable to drug intervention to mitigate skeletal tissue degeneration (e.g., osteoarthritis and osteoporosis). We highlight recent findings on a number of druggable epigenetic regulators, including DNA methyltransferases (e.g., DNMT1, DNMT3A, and DNMT3B) and hydroxylases (e.g., TET1, TET2, and TET3), histone methyltransferases (e.g., EZH1, EZH2, and DOT1L) as well as histone deacetylases (e.g., HDAC3, HDAC4, and HDAC7) and histone acetyl readers (e.g., BRD4) in relation to the development of bone or cartilage regenerative drug therapies. We also review how histone mutations lead to epigenomic catastrophe and cause musculoskeletal tumors. The combined body of molecular and genetic studies focusing on epigenetic regulators indicates that these proteins are critical for normal skeletogenesis and viable candidate drug targets for short-term local pharmacological strategies to mitigate musculoskeletal tissue degeneration.

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Section: The Basics Of Epigeneticsmentioning

confidence: 99%

Epigenetics as a New Frontier in Orthopedic Regenerative Medicine and Oncology

Wijnen

Westendorf

2019

Journal Orthopaedic Research

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“…MicroRNAs (miRNAs) are a class of non-coding, small-molecule, single-stranded RNAs (generally 18 to 22 nucleotides in length) that are highly evolutionarily conserved. They are involved in the regulation of various pathophysiological processes, such as cell proliferation, differentiation and apoptosis 19 , 20 . miRNAs play important roles in the development and progression of many tumors by participating in gene regulation 21 , 22 .…”

Section: Introductionmentioning

confidence: 99%

The expression and function of miR-424 in infantile skin hemangioma and its mechanism

Yang

Dai

et al. 2017

Sci Rep

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Infantile hemangioma is the most common benign tumor in infants. Many studies have confirmed that basic fibroblast growth factor (bFGF) and its key receptor FGFR1 are highly expressed in hemangioma. Moreover, several miRNAs can regulate angiogenesis. In this regard, miR-424 often plays a role as tumor suppressor gene. This study was designed to investigate the mechanism of miR-424 in infantile skin hemangioma. Our results showed low expression of miR-424 in infantile skin hemangioma tissues, and that miR-424 overexpression downregulated FGFR1 expression in hemangioma-derived endothelial cells, while miR-424 inhibition upregulated FGFR1 expression. Luciferase reporter analysis confirmed that FGFR1 was a target gene of miR-424. CCK-8, flow cytometry, transwell migration and tube formation assays demonstrated that miR-424 overexpression inhibited cell proliferation, migration and tube formation, at least in part by blocking the bFGF/FGFR1 pathway. In contrast, miR-424 inhibition significantly enhanced these functions. Furthermore, miR-424 overexpression significantly inhibited ERK1/2 phosphorylation, whereas miR-424 inhibition enhanced ERK1/2 phosphorylation. In conclusion, miR-424 could suppress the bFGF/FGFR1 pathway, thereby inhibit ERK1/2 phosphorylation, and thus inhibit cell proliferation, migration and tube formation capabilities and the development of infantile skin hemangioma.

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“…transforming growth factor ␤ (TGF-␤), bone morphogenic protein (BMP), wingless/integrated (WNT) (16). Recent studies have also identified epigenetic processes, including histone acetylation and methylation, that contribute to the regulation of differentiation and maturation of mesenchymal progenitors, chondrocytes, and osteoblasts (17)(18)(19)(20)(21)(22)(23)(24).…”

mentioning

confidence: 99%

Loss of histone methyltransferase Ezh2 stimulates an osteogenic transcriptional program in chondrocytes but does not affect cartilage development

Camilleri

Dudakovic

Riester

et al. 2018

Journal of Biological Chemistry

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Edited by Joel M. Gottesfeld Ezh2 is a histone methyltransferase that suppresses osteoblast maturation and skeletal development. We evaluated the role of Ezh2 in chondrocyte lineage differentiation and endochondral ossification. Ezh2 was genetically inactivated in the mesenchymal, osteoblastic, and chondrocytic lineages in mice using the Prrx1-Cre, Osx1-Cre, and Col2a1-Cre drivers, respectively. WT and conditional knockout mice were phenotypically assessed by gross morphology, histology, and micro-CT imaging. Ezh2-deficient chondrocytes in micromass culture models were evaluated using RNA-Seq, histologic evaluation, and Western blotting. Aged mice with Ezh2 deficiency were also evaluated for premature development of osteoarthritis using radiographic analysis. Ezh2 deficiency in murine chondrocytes reduced bone density at 4 weeks of age but caused no other gross developmental effects. Knockdown of Ezh2 in chondrocyte micromass cultures resulted in a global reduction in trimethylation of histone 3 lysine 27 (H3K27me3) and altered differentiation in vitro. RNA-Seq analysis revealed enrichment of an osteogenic gene expression profile in Ezh2-deficient chondrocytes. Joint development proceeded normally in the absence of Ezh2 in chondrocytes without inducing excessive hypertrophy or premature osteoarthritis in vivo. In summary, loss of Ezh2 reduced H3K27me3 levels, increased the expression of osteogenic genes in chondrocytes, and resulted in a transient post-natal bone phenotype. Remarkably, Ezh2 activity is dispensable for normal chondrocyte maturation and endochondral ossification in vivo, even though it appears to have a critical role during early stages of mesenchymal lineage commitment. cro ARTICLE

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MiR-101 Targets the EZH2/Wnt/β-Catenin the Pathway to Promote the Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells

Cited by 50 publications

References 44 publications

Epigenetics as a New Frontier in Orthopedic Regenerative Medicine and Oncology

Epigenetics as a New Frontier in Orthopedic Regenerative Medicine and Oncology

The expression and function of miR-424 in infantile skin hemangioma and its mechanism

Loss of histone methyltransferase Ezh2 stimulates an osteogenic transcriptional program in chondrocytes but does not affect cartilage development

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