MiR‐137 knockdown promotes the osteogenic differentiation of human adipose‐derived stem cells via the LSD1/BMP2/SMAD4 signaling network

Ma, Xu; Fan, Cong; Wang, Yuejun; Du, Yangge; Zhu, Yuan; Liu, Hao; Lv, Longwei; Liu, Yunsong; Zhou, Yongsheng

doi:10.1002/jcp.29006

Cited by 21 publications

(37 citation statements)

References 42 publications

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“…Smad4 is the only common Smad involved in BMP2 signaling. 24,25 Conditional deletion of Smad4 in osteoblasts leads to reduced bone mineral density, decreased bone volume, a decreased bone formation rate, and a reduced number of osteoblasts. 26 Controlling Smad4 is a good way to regulate bone formation.…”

Section: Introductionmentioning

confidence: 99%

<p>The Role of Tantalum Nanoparticles in Bone Regeneration Involves the BMP2/Smad4/Runx2 Signaling Pathway</p>

Zhang¹,

Liu²,

Wang³

et al. 2020

IJN

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Background: In recent years, nanomaterials have been increasingly developed and applied in the field of bone tissue engineering. However, there are few studies on the induction of bone regeneration by tantalum nanoparticles (Ta NPs) and no reports on the effects of Ta NPs on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and the underlying mechanisms. The main purpose of this study was to investigate the effects of Ta NPs on bone regeneration and BMSC osteogenic differentiation and the underlying mechanisms. Materials and Methods: The effects of Ta NPs on bone regeneration were evaluated in an animal experiment, and the effects of Ta NPs on osteogenic differentiation of BMSCs and the underlying mechanisms were evaluated in cell experiments. In the animal experiment, hematoxylin-eosin (HE) staining and hard-tissue section analysis showed that Ta NPs promoted bone regeneration, and immunohistochemistry revealed elevated expression of BMP2 and Smad4 in cells cultured with Ta NPs. Results: The results of the cell experiments showed that Ta NPs promoted BMSC proliferation, alkaline phosphatase (ALP) activity, BMP2 secretion and extracellular matrix (ECM) mineralization, and the expression of related osteogenic genes and proteins (especially BMP2, Smad4 and Runx2) was upregulated under culture with Ta NPs. Smad4 expression, ALP activity, ECM mineralization, and osteogenesis-related gene and protein expression decreased after inhibiting Smad4. Conclusion: These data suggest that Ta NPs have an osteogenic effect and induce bone regeneration by activating the BMP2/Smad4/Runx2 signaling pathway, which in turn causes BMSCs to undergo osteogenic differentiation. This study provides insight into the molecular mechanisms underlying the effects of Ta NPs in bone regeneration.

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Section: Introductionmentioning

confidence: 99%

<p>The Role of Tantalum Nanoparticles in Bone Regeneration Involves the BMP2/Smad4/Runx2 Signaling Pathway</p>

Zhang¹,

Liu²,

Wang³

et al. 2020

IJN

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“…MiR-137 reversely regulates hASC differentiation along osteoblastic lineage in vitro Our previous study displayed an overall downward expression trend of miR-137 in hASCs during the osteoblastic induction and identi ed its negative role in this biological process [32]. Since lacking research on the osteogenic function of miR-137, rstly, we re-veri ed the reliability of our previous results.…”

Section: Resultssupporting

confidence: 72%

“…In contrast, NOTCH1 upregulates BMP2 expression in human aortic valve interstitial cells through the stimulation of NF-κB [47]. Our previous study con rmed that miR-137 knockdown induced BMP2-SMADA4 pathway through the downregulation of LSD1 dependently or independently [32], which coincides with the studies stating that LSD1 inhibition leads to increased BMP2 expression [48,49]. Accordingly, we postulate a signaling network entailing NOTCH1-HES1, LSD1 and BMP2-SMAD4 pathways to unveil the miR-137 modulation on the osteogenesis of hASCs.…”

mentioning

confidence: 82%

“…that miR-137 regulates cell proliferation, differentiation [24][25][26][27][28], and neuronal maturation [29][30][31] in adult or mouse stem cells. Nevertheless, during the process of hASCs differentiating into osteoblastic lineage, the functions and epigenetic mechanisms of miR-137 have not been investigated except for our previous study [32], in which we disclose part of the mechanisms as the coordination between lysine-speci c histone demethylase 1 (LSD1) and BMP2-mothers against decapentaplegic homolog 4 (SMAD4) pathway. Considering that the relationships of osteogenesis-associated signals are complex and diverse and massive molecules participating in the LSD1/BMP2/SMADA4 network remain unascertained, we need to further clarify the regulatory mechanisms of miR-137 on the osteogenesis.…”

mentioning

confidence: 89%

“…The 3' untranslated region (3' UTR) alignments of the target regions in NOTCH1 were predicted by TargetScan and RNA22. Reporter vectors were constructed based on the previous method [32]. The 3' UTR sequences of NOTCH1, which contained the possible binding sites of miR-137, were PCR ampli ed and then inserted into pEZX-MT06 vectors (GeneCopoeia, Rockville, MD, USA) to create NOTCH1-WT (wild-type NOTCH1) luciferase reporter plasmids.…”

Section: Dual-luciferase Reporter Assaymentioning

confidence: 99%

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A NOTCH1/LSD1/BMP2 Co-Regulatory Network Mediated by miR-137 Negatively Regulates Osteogenesis of Human Adipose-Derived Stem Cells

Fan

Wang

et al. 2020

Preprint

Self Cite

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Background: MicroRNAs have been recognized as critical regulators for the osteoblastic lineage differentiation of human adipose-derived stem cells (hASCs). Previously, we have displayed that silencing of miR-137 enhances the osteoblastic differentiation potential of hASCs partly through the coordination of lysine-specific histone demethylase 1 (LSD1), bone morphogenetic protein 2 (BMP2), and mothers against decapentaplegic homolog 4 (SMAD4). However, still numerous molecules involved in the osteogenic regulation of miR-137 remain unknown. This study aimed to further elucidate the epigenetic mechanisms of miR-137 on the osteogenic differentiation of hASCs.Methods: hASCs transfected with miR-137 overexpression or knockdown lentiviruses were used to assess the osteogenic capacity by testing the alkaline phosphatase activity, matrix mineralization degree, relative expression level of osteogenesis-associated genes and ectopic osteogenesis in nude mice. Dual-luciferase reporter assay was performed to examine the targeting of the 3' untranslated region (3' UTR) of NOTCH1 by miR-137. Interrelationships of signaling pathways of NOTCH1-hairy and enhancer of split 1 (HES1), LSD1, and BMP2-SMAD4 were thoroughly investigated by separate knockdown of NOTCH1, LSD1, and BMP2.Results: We confirmed that miR-137 directly targeted the 3' UTR of NOTCH1 while positively regulated HES1. After knocking down NOTCH1 or BMP2 individually, we found that these two signals formed a positive feedback loop and activated LSD1. In addition, LSD1 knockdown induced the expression of NOTCH1 while suppressed HES1.Conclusions: Collectively, we proposed a NOTCH1/LSD1/BMP2 co-regulatory signaling network to elucidate the modulation of miR-137 on the osteoblastic differentiation of hASCs, thus providing mechanism-based rationale for miRNA-targeted therapy of bone defect.

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miR-708-3p targetedly regulates LSD1 to promote osteoblast differentiation of hPDLSCs in periodontitis

Shao,

Liu,

Zou

et al. 2024

Odontology

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Periodontitis (PD) is a multifactorial inflammatory disease associated with periodontopathic bacteria. Lysine-specific demethylase 1 (LSD1), a type of histone demethylase, has been implicated in the modulation of the inflammatory response process in oral diseases by binding to miRNA targets. This study investigates the molecular mechanisms by which miRNA binds to LSD1 and its subsequent effect on osteogenic differentiation. First, human periodontal ligament stem cells (hPDLSCs) were isolated, cultured, and characterized. These cells were then subjected to lipopolysaccharide (LPS) treatment to induce inflammation, after which osteogenic differentiation was initiated. qPCR and western blot were employed to monitor changes in LSD1 expression. Subsequently, LSD1 was silenced in hPDLSCs to evaluate its impact on osteogenic differentiation. Through bioinformatics and dual luciferase reporter assay, miR-708-3p was predicted and confirmed as a target miRNA of LSD1. Subsequently, miR-708-3p expression was assessed, and its role in hPDLSCs in PD was evaluated through overexpression. Using chromatin immunoprecipitation (ChIP) and western blot assay, we explored the potential regulation of osterix (OSX) transcription by miR-708-3p and LSD1 via di-methylated H3K4 (H3K4me2). Finally, we investigated the role of OSX in hPDLSCs. Following LPS treatment of hPDLSCs, the expression of LSD1 increased, but this trend was reversed upon the induction of osteogenic differentiation. Silencing LSD1 strengthened the osteogenic differentiation of hPDLSCs. miR-708-3p was found to directly bind to and negatively regulate LSD1, leading to the repression of OSX transcription through demethylation of H3K4me2. Moreover, overexpression of miR-708-3p was found to promote hPDLSCs osteogenic differentiation in inflammatory microenvironment. However, the protective effect was partially attenuated by reduced expression of OSX. Our findings indicate that miR-708-3p targetedly regulates LSD1 to enhance OSX transcription via H3K4me2 methylation, ultimately promoting hPDLSCs osteogenic differentiation.

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MiR‐137 knockdown promotes the osteogenic differentiation of human adipose‐derived stem cells via the LSD1/BMP2/SMAD4 signaling network

Cited by 21 publications

References 42 publications

<p>The Role of Tantalum Nanoparticles in Bone Regeneration Involves the BMP2/Smad4/Runx2 Signaling Pathway</p>

<p>The Role of Tantalum Nanoparticles in Bone Regeneration Involves the BMP2/Smad4/Runx2 Signaling Pathway</p>

A NOTCH1/LSD1/BMP2 Co-Regulatory Network Mediated by miR-137 Negatively Regulates Osteogenesis of Human Adipose-Derived Stem Cells

miR-708-3p targetedly regulates LSD1 to promote osteoblast differentiation of hPDLSCs in periodontitis

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