The transcription factor snail regulates osteogenic differentiation by repressing Runx2 expression

Bone ◽  
2010 ◽  
Vol 46 (6) ◽  
pp. 1498-1507 ◽  
Author(s):  
Su Jin Park ◽  
Seung-Hyun Jung ◽  
Gadi Jogeswar ◽  
Hyun-Mo Ryoo ◽  
Jong In Yook ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Osteogenic Differentiation ◽  
Runx2 Expression

scholarly journals MicroRNA treatment modulates osteogenic differentiation potential of mesenchymal stem cells derived from human chorion and placenta

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kulisara Marupanthorn ◽  
Chairat Tantrawatpan ◽  
Pakpoom Kheolamai ◽  
Duangrat Tantikanlayaporn ◽  
Sirikul Manochantr
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Transcription Factor ◽  
Osteogenic Differentiation ◽  
Differentiation Potential ◽  
Osteogenic Gene Expression ◽  
Osteogenic Gene

AbstractMesenchymal stem cells (MSCs) are important in regenerative medicine because of their potential for multi-differentiation. Bone marrow, chorion and placenta have all been suggested as potential sources for clinical application. However, the osteogenic differentiation potential of MSCs derived from chorion or placenta is not very efficient. Bone morphogenetic protein-2 (BMP-2) plays an important role in bone development. Its effect on osteogenic augmentation has been addressed in several studies. Recent studies have also shown a relationship between miRNAs and osteogenesis. We hypothesized that miRNAs targeted to Runt-related transcription factor 2 (Runx-2), a major transcription factor of osteogenesis, are responsible for regulating the differentiation of MSCs into osteoblasts. This study examines the effect of BMP-2 on the osteogenic differentiation of MSCs isolated from chorion and placenta in comparison to bone marrow-derived MSCs and investigates the role of miRNAs in the osteogenic differentiation of MSCs from these sources. MSCs were isolated from human bone marrow, chorion and placenta. The osteogenic differentiation potential after BMP-2 treatment was examined using ALP staining, ALP activity assay, and osteogenic gene expression. Candidate miRNAs were selected and their expression levels during osteoblastic differentiation were examined using real-time RT-PCR. The role of these miRNAs in osteogenesis was investigated by transfection with specific miRNA inhibitors. The level of osteogenic differentiation was monitored after anti-miRNA treatment. MSCs isolated from chorion and placenta exhibited self-renewal capacity and multi-lineage differentiation potential similar to MSCs isolated from bone marrow. BMP-2 treated MSCs showed higher ALP levels and osteogenic gene expression compared to untreated MSCs. All investigated miRNAs (miR-31, miR-106a and miR148) were consistently downregulated during the process of osteogenic differentiation. After treatment with miRNA inhibitors, ALP activity and osteogenic gene expression increased over the time of osteogenic differentiation. BMP-2 has a positive effect on osteogenic differentiation of chorion- and placenta-derived MSCs. The inhibition of specific miRNAs enhanced the osteogenic differentiation capacity of various MSCs in culture and this strategy might be used to promote bone regeneration. However, further in vivo experiments are required to assess the validity of this approach.

miRNA-126 Inhibits Osteogenic Differentiation of Rat Bone Marrow Mesenchymal Stem Cells (BMSCs)

2022 ◽  
Vol 12 (4) ◽  
pp. 794-799
Author(s):  
Le Chang ◽  
Wei Duan ◽  
Chuang Wang ◽  
Jian Zhang
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Osteogenic Differentiation ◽  
Mrna Level ◽  
Alizarin Red ◽  
Runx2 Expression ◽  
Alp Activity ◽  
Smad4 Protein ◽  
Marrow Mesenchymal Stem Cells

This study was to determine whether microRNA (miRNA)-126 regulates osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Rat BMSCs were extracted and stimulated for osteogenic differentiation. Functional experiments were conducted to assess miR-126’s impact on BMSCs differentiation. Western blot and RT-qPCR determined miR-126 expression. ALP activity detection and alizarin red staining detection were also performed. After osteogenic differentiation of BMSCs, miR-126 expression was gradually decreased over time. Overexpression of miR-26 decreased ALP activity, Notch signaling activity as well as declined Runx2 expression and calcium Salt nodules after treatment. Importantly, we found that Smad4 serves as a target of miR-126 while upregulation of the miRNA was accompanied with the decreased Smad4 protein expression without affecting the Smad4 mRNA level. In conclusion, miR-126 restrains osteogenic differentiation through inhibition of SMAD4 signaling, providing a novel insight into the mechanism.

scholarly journals The secreted protein DEL-1 activates a β3 integrin–FAK–ERK1/2–RUNX2 pathway and promotes osteogenic differentiation and bone regeneration

2020 ◽  
Vol 295 (21) ◽  
pp. 7261-7273 ◽  
Author(s):  
Da-Yo Yuh ◽  
Tomoki Maekawa ◽  
Xiaofei Li ◽  
Tetsuhiro Kajikawa ◽  
Khalil Bdeir ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Bone Regeneration ◽  
Osteogenic Differentiation ◽  
Secreted Protein ◽  
Dependent Manner ◽  
Point Mutant ◽  
Rgd Motif ◽  
Β3 Integrin ◽  
Defective Bone

The integrin-binding secreted protein developmental endothelial locus-1 (DEL-1) is involved in the regulation of both the initiation and resolution of inflammation in different diseases, including periodontitis, an oral disorder characterized by inflammatory bone loss. Here, using a mouse model of bone regeneration and in vitro cell-based mechanistic studies, we investigated whether and how DEL-1 can promote alveolar bone regeneration during resolution of experimental periodontitis. Compared with WT mice, mice lacking DEL-1 or expressing a DEL-1 variant with an Asp-to-Glu substitution in the RGD motif (“RGE point mutant”), which does not interact with RGD-dependent integrins, exhibited defective bone regeneration. Local administration of DEL-1 or of its N-terminal segment containing the integrin-binding RGD motif, but not of the RGE point mutant, reversed the defective bone regeneration in the DEL-1–deficient mice. Moreover, DEL-1 (but not the RGE point mutant) promoted osteogenic differentiation of MC3T3-E1 osteoprogenitor cells or of primary calvarial osteoblastic cells in a β3 integrin–dependent manner. The ability of DEL-1 to promote in vitro osteogenesis, indicated by induction of osteogenic genes such as the master transcription factor Runt-related transcription factor-2 (Runx2) and by mineralized nodule formation, depended on its capacity to induce the phosphorylation of focal adhesion kinase (FAK) and of extracellular signal-regulated kinase 1/2 (ERK1/2). We conclude that DEL-1 can activate a β3 integrin–FAK–ERK1/2–RUNX2 pathway in osteoprogenitors and promote new bone formation in mice. These findings suggest that DEL-1 may be therapeutically exploited to restore bone lost due to periodontitis and perhaps other osteolytic conditions.

Transcription factor 7-like 2 promotes osteogenic differentiation and boron-induced bone repair via lipocalin 2

2020 ◽  
Vol 110 ◽  
pp. 110671
Author(s):  
Chengcheng Yin ◽  
Xiaoshi Jia ◽  
Qin Zhao ◽  
Zifan Zhao ◽  
Jinyang Wang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Osteogenic Differentiation ◽  
Bone Repair ◽  
Lipocalin 2

scholarly journals Identification of a Novel Transcription Factor Required for Osteogenic Differentiation of Mesenchymal Stem Cells

2019 ◽  
Vol 28 (6) ◽  
pp. 370-383 ◽  
Author(s):  
Francesca Querques ◽  
Anna D'Agostino ◽  
Carmine Cozzolino ◽  
Luca Cozzuto ◽  
Barbara Lombardo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Transcription Factor ◽  
Osteogenic Differentiation

Satb2 expression in Foxc1-promoted osteogenic differentiation of MC3T3-E1 cells is negatively regulated by microRNA-103-3p

2019 ◽  
Vol 51 (6) ◽  
pp. 588-597 ◽  
Author(s):  
Hongzhou Shen ◽  
Chenpei Lu ◽  
Jun Shi ◽  
Hongliang Li ◽  
Jiawen Si ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Osteogenic Differentiation ◽  
Cell Fate ◽  
Mirna Expression ◽  
Early Stage ◽  
Expression Profiles ◽  
Negative Regulator ◽  
Cranial Bone ◽  
Luciferase Assay ◽  
Forkhead Transcription Factor

AbstractThe forkhead transcription factor C1 (Foxc1) is a cell-fate-determining factor that controls cranial bone development and osteogenic differentiation. Previously, it was demonstrated that various microRNAs (miRNAs) play important roles in osteogenesis and regulate the complex process of osteogenic differentiation. However, it remains unclear how miRNA expression changes during Foxc1-promoted osteogenic differentiation. In this study, we successfully overexpressed the Foxc1 gene in MC3T3-E1 cells and investigated the alterations in the miRNA expression profile on day 3 after osteogenic induction by using a miRNA microarray. Nine downregulated miRNAs and eight upregulated miRNAs were found to be differentially expressed. Among these miRNAs, miR-103-3p was consistently downregulated in the Foxc1-overexpressing MC3T3-E1 cells and was identified as a negative regulator of osteogenic differentiation by using a gain- and lose-of-function assay. The special AT-rich sequence-binding protein 2 (Satb2), a pivotal osteogenic transcription factor, was identified as the miR-103-3p targeting gene and was verified by real-time polymerase chain reaction, western blot analysis, and luciferase assay. Overexpression of miR-103-3p markedly inhibited the expression of Satb2 and attenuated Foxc1-promoted osteogenic differentiation. Taken together, our results elucidated the miRNA expression profiles of MC3T3-E1 cells in the early stage of Foxc1-promoted osteogenic differentiation and suggested that miR-103-3p acts as a negative regulator of the osteogenic differentiation of MC3T3-E1 cells by directly targeting Satb2.

scholarly journals PLZF targets developmental enhancers for activation during osteogenic differentiation of human mesenchymal stem cells

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Shuchi Agrawal Singh ◽  
Mads Lerdrup ◽  
Ana-Luisa R Gomes ◽  
Harmen JG van de Werken ◽  
Jens Vilstrup Johansen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Transcription Factor ◽  
Osteogenic Differentiation ◽  
Human Mesenchymal Stem Cells ◽  
High Expression ◽  
Molecular Function

The PLZF transcription factor is essential for osteogenic differentiation of hMSCs; however, its regulation and molecular function during this process is not fully understood. Here, we revealed that the ZBTB16 locus encoding PLZF, is repressed by Polycomb (PcG) and H3K27me3 in naive hMSCs. At the pre-osteoblast stage of differentiation, the locus lost PcG binding and H3K27me3, gained JMJD3 recruitment, and H3K27ac resulting in high expression of PLZF. Subsequently, PLZF was recruited to osteogenic enhancers, influencing H3K27 acetylation and expression of nearby genes important for osteogenic function. Furthermore, we identified a latent enhancer within the ZBTB16/PLZF locus itself that became active, gained PLZF, p300 and Mediator binding and looped to the promoter of the nicotinamide N-methyltransferase (NNMT) gene. The increased expression of NNMT correlated with a decline in SAM levels, which is dependent on PLZF and is required for osteogenic differentiation.

Osteogenic Differentiation of Human Adipose Tissue-Derived Stem Cells Is Modulated by the miR-26a Targeting of the SMAD1 Transcription Factor

2007 ◽  
Vol 23 (2) ◽  
pp. 287-295 ◽  
Author(s):  
Ettore Luzi ◽  
Francesca Marini ◽  
Silvia Carbonell Sala ◽  
Isabella Tognarini ◽  
Gianna Galli ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Adipose Tissue ◽  
Osteogenic Differentiation ◽  
Human Adipose Tissue

Lineage-Specific RUNX2 Super-Enhancer Activates MYC Via Translocation (6;8) to Promote the Development of Blastic Plasmacytoid Dendritic Cell Neoplasm

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 761-761
Author(s):  
Sho Kubota ◽  
Kenji Tokunaga ◽  
Tomohiro Umezu ◽  
Takako Yokomizo ◽  
Motohiko Oshima ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Colony Formation ◽  
Research Funding ◽  
Plasmacytoid Dendritic Cell ◽  
Chromosome 6 ◽  
Wild Type ◽  
Runx2 Expression ◽  
Signature Genes ◽  
Super Enhancer ◽  
Cell Neoplasm

Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematological malignancy, characteristic of skin lesions followed by hematopoietic organ dissemination. The cell of origin of which is considered to be precursors of plasmacytoid dendritic cells (pDCs). BPDCN cells show high frequencies of mutations in TET2 and p53; however, the molecular mechanisms underlying the pathogenesis of BPDCN have not yet been elucidated. RUNX2 transcription factor, located on chromosome 6p21, is critical for the differentiation of pDCs and the enhancer of RUNX2 is activated in pDCs. Since translocation (6;8)(p21;q24), which is a rare, but specific anomaly for BPDCN, involves regions adjacent to RUNX2 and MYC, we demonstrate that the pDC-specific RUNX2 super-enhancer activates the expression of RUNX2, which functions as a lineage-survival transcription factor, but also is hijacked to activate expression of MYC via t(6;8) in BPDCN cells, and that RUNX2 and MYC promote the initiation and propagation of BPDCN by generating a novel mouse model. In order to identify the breakpoint of t(6;8)(p21;q24), we first performed fluorescent in situ hybridization and whole genome sequencing of CAL-1 cells, a BPDCN cell line, and identified a fusion point of chromosome translocation between chromosome 8 in 69 kilobases (kb) downstream of MYC and chromosome 6, which was 58 kb centromeric to a long and clustered super-enhancer of RUNX2 (791 kb upstream of RUNX2) defined by chromatin immunoprecipitation sequencing using anti-H3K27ac or anti-BRD4 antibodies. As we observed the enhanced levels of MYC and RUNX2 expression in BPDCN cells in patients and CAL-1 cells, we knocked down expression of MYC or RUNX2 using distinct shRNA vectors in CAL-1 cells. We found that the knockdown of MYC and/or RUNX2 significantly impaired colony formation capacities. By performing microarray analysis, we found that RUNX2 knockdown significantly reduced expression of pDCs-signature genes in CAL-1 cells, accompanied with the enhanced apoptosis in CAL-1 cells, implying that RUNX2 is critical for the survival of BPDCN cells due to expressing pDCs-signature genes. To evaluate the function of RUNX2 super-enhancer, we examined how BRD4 inhibition affected the proliferative capacities of CAL-1 cells in vitro. Indeed, we found that JQ1-treated CAL-1 cells showed significantly lower H3K27ac modification levels at the RUNX2 super-enhancer and significantly decreased levels of MYC and RUNX2 expression, resulting in the impaired colony formation capacities, which were rescued by the ectopic expression of both RUNX2 and MYC. We also genetically deleted the mutant-allele super-enhancer of RUNX2 on der(8) (seRUNX2der8), but not that on chromosome 6, using CRISPR-Cas9 vectors. After establishing single cell clones, all seRUNX2der8-deleted clones showed markedly impaired colony formation capacities accompanied with the reduced expression of MYC. Taken together, the seRUNX2der8 directly activates the expression of MYC to promote the development of BPDCN, which is reversed by the inhibition of BRD4. We finally examined whether the transduction of MYC and RUNX2 was sufficient for the initiation of BPDCN in vivo in the absence of Tet2 and p53. We purified Lineage-Sca-1+c-Kit+ stem/progenitor cells from wild-type and Tet2/p53 double knockout (DKO) mice and infected them with MYC- and RUNX2-retrovirus vectors. After a 9-day culture promoting the differentiation of pDCs, we transplanted transduced cells into recipient mice together with wild-type competitor cells. MYC+RUNX2-DKO mice showed robust leukocytosis, anemia, and thrombocytopenia and died by two months post-transplantation following the expansion of immature leukemic blasts. A FACS analysis showed that these leukemic blasts were CD11b-CD11cmid/+B220+Bst2+, which was consistent with the murine pDCs immunophenotype, and massively infiltrated the spleen and liver tissues. MYC+RUNX2-DKO leukemic cells were transplantable in secondary recipient mice with the same immunophenotype. Thus, the transduction of MYC and RUNX2 is sufficient to initiate the transformation of lethal BPDCN-like disease in mice lacking Tet2 and p53. We are now exploring the molecular mechanism of how MYC and RUNX2 collaborate to initiate the formation of BPDCN by performing RNA-sequencing analysis and transplantation assay of BPDCN-initiating cells. Disclosures Asou: Asahi Kasei Pharma Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; SRL Inc.: Consultancy; Yakult Honsha Co., Ltd.: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Speakers Bureau; Astellas Pharma Inc.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding. Ohyashiki:Pfizer KK,: Honoraria, Research Funding; MSD,: Honoraria, Research Funding; Kyowakko Kirin KK,: Research Funding; Jansen Pharma KK,: Research Funding; Novartis KK,: Honoraria, Research Funding; Celegene KK,: Honoraria, Research Funding; Takeda Pharmaceutical KK,: Honoraria, Research Funding; Taiho Pharmaceutical KK: Honoraria, Research Funding; Asahikase: Research Funding; Asteras KK,: Research Funding; Nihon-Seiyaku,: Research Funding; Eizai,: Research Funding; Dainippon Sumitomo KK,: Honoraria, Research Funding; Nippon-shinyaku,: Honoraria, Research Funding; Bristol Meyer Squibb KK,: Honoraria, Research Funding; Ono Pharmaceutical KK,: Honoraria, Research Funding; Chugai KK,: Honoraria, Research Funding.

Exosome-Derived miR21/SMAD7 Derived from Donor Osteoporosis Mesenchymal Stem Cells Inhibits Osteogenic Differentiation of Reconstituted Hosts

2019 ◽  
Vol 9 (10) ◽  
pp. 1346-1354
Author(s):  
Jie Chen ◽  
Yongsheng Luo ◽  
Ting Li ◽  
Wenbo Yang ◽  
Wen Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Osteogenic Differentiation ◽  
Runx2 Expression ◽  
Alp Activity ◽  
Marrow Mesenchymal Stem Cells ◽  
Smad7 Expression ◽  
Different Sources ◽  
Adult Mscs ◽  
Normal Adults

Exogenous bone marrow mesenchymal stem cells (MSCs) can regulate osteogenic differentiation. MicroRNA-21 has been shown to target SMAD7. This study explored the mechanism by which miR-21/SMAD7 inhibits osteogenic differentiation from exosomes secreted by osteoporosis patients-derived MSCs. Exosomes were obtained from MSCs and miR-21 expression was detected. Normal MSCs were treated with exosomes secreted by MSCs from different sources for osteogenic differentiation followed by detection of ALP, Bglap and Runx2 level and ALP activity. Normal MSCs were divided into three groups, which were treated with exosomes from normal adult MSCs, osteoporosis patients-derived MSCs and osteoporosis patients-derived MSCs + SMAD7 overexpression followed by analysis of the mRNA expression of ALP, Bglap and Runx2 by qRT-PCR and ALP activity. miR-21 expression in exosomes from osteoporosis patients-derived MSCs was significantly higher than that from normal adults MSCs. After treatment with exosomes from osteoporosis patients-derived MSCs, Runx2 expression and ALP activity was significantly decreased. SMAD7 expression in osteoporosis patients was significantly lower than that in normal adults. The expression of ALP, Bglap and Runx2 is significantly decreased after overexpression of SMAD7. SMAD7 is a target gene of miR-21 and plays a role in inhibiting osteogenic differentiation induced by exosomes from osteoporosis-derived MSCs.

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