MicroRNA-125b-5p inhibits proliferation and promotes adipogenic differentiation in 3T3-L1 preadipocytes

Ouyang, Deqin; Ye, Yaqiong; Guo, Dongguang; Yu, Xiaofang; Chen, Jian; Qi, Junjie; Tan, Xiaojie; Zhang, Yuan; Ma, Yue; Li, Yugu

doi:10.1093/abbs/gmv024

Cited by 31 publications

(19 citation statements)

References 43 publications

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“…Furthermore, our results revealed that knockdown of Smad4 gene or overexpression of miR-144-3p inhibited the proliferation of MSCs (Fig. 6), which is consistent with Dan et al who have reported that miR-125b-5p inhibits proliferation in 3T3-L1 preadipocytes by targeting Smad4 [35]. Additionally, we found that Smad4 knockdown blocks the effects of miR-144-3p ( Fig.…”

Section: Discussionsupporting

confidence: 90%

MiR‐144‐3p regulates osteogenic differentiation and proliferation of murine mesenchymal stem cells by specifically targeting Smad4

et al. 2016

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Despite extensive research on osteoblast differentiation and proliferation in mesenchymal stem cells (MSCs), the accurate mechanism remains to be further elucidated. MicroRNAs have been reported to be key regulators of osteoblast differentiation and proliferation. Here, we found that miR‐144‐3p is down‐regulated during osteoblast differentiation of C3H10T1/2 cells. Overexpression of miR‐144‐3p inhibited osteogenic differentiation, whereas inhibition of miR‐144‐3p reversed this process. Furthermore, miR‐144‐3p inhibited the proliferation of C3H10T1/2 cells by arresting cells at the G0/G1 phase. Results from bioinformatics analysis, luciferase assay and western blotting demonstrated that miR‐144‐3p directly targeted Smad4. Additionally, Smad4 knockdown blocks the effects of miR‐144‐3p inhibitor. Therefore, we conclude that miR‐144‐3p negatively regulates osteogenic differentiation and proliferation of C3H10T1/2 cells by targeting Smad4.

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Section: Discussionsupporting

confidence: 90%

MiR‐144‐3p regulates osteogenic differentiation and proliferation of murine mesenchymal stem cells by specifically targeting Smad4

et al. 2016

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“…Although the importance of Smad4 in osteogenic differentiation has been proposed in certain reports, including a study describing the reduction of bone mineral density, bone volume, and osteoblast numbers in osteoblast‐specific Smad4 conditional KO mice and one on the role of miR‐144‐3p‐targeting Smad4 in osteogenic differentiation , our findings extend our knowledge about the molecular mechanism of Smad4 as a positive factor in the osteogenic differentiation of MSCs. In contrast, a possible role of Smad4 in adipogenic differentiation was predicted by a previous report that miR‐125b‐5p could potentially target Smad4 in preadipocyte 3T3‐L1 cells , but this report did not demonstrate the exact mechanism of Smad4 as a negative factor in adipogenic differentiation. Therefore, our results provide a clue about the inverse reciprocal regulation between the osteogenesis and adipogenesis of MSCs.…”

Section: Discussioncontrasting

confidence: 83%

A Reciprocal Role of the Smad4-Taz Axis in Osteogenesis and Adipogenesis of Mesenchymal Stem Cells

et al. 2018

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Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into mature cells of various cell types. Although the differentiation process of MSCs requires lineage-specific transcription factors, the exact molecular mechanism that determines MSCs differentiation is not clearly addressed. Here, we demonstrate a Smad4-Taz axis as a new intrinsic regulator for adipoosteogenic differentiation of MSCs and show that this function of Smad4 is independent of the transforming growth factor-β signal. Smad4 directly bound to the Taz protein and facilitated nuclear localization of Taz through its nuclear localization signal. Nuclear retention of Taz by direct binding to Smad4 increased expression of osteogenic genes through enhancing Taz-runt-related transcription factor 2 (Runx2) interactions in the C3H10T1/2 MSC cell line and preosteoblastic MC3T3-E1 cells, whereas it suppressed expression of adipogenic genes through promoting Tazperoxisome proliferator-activated receptor-γ (PPARγ) interaction in C3H10T1/2 and preadipogenic 3T3-L1 cells. A reciprocal role of the Smad4 in osteogenic and adipogenic differentiation was also observed in human adipose tissue-derived stem cells (hASCs). Consequently, Smad4 depletion in C3H10T1/2 and hASCs reduced nuclear retention of Taz and thus caused the decreased interaction with Runx2 or PPARγ, resulting in delayed osteogenesis or enhanced adipogenesis of the MSC. Therefore, these findings provide insight into a novel function of Smad4 to regulate the balance of MSC lineage commitment through reciprocal targeting of the Taz protein in osteogenic and adipogenic differentiation pathways. STEM CELLS 2019;37:368-381 SIGNIFICANCE STATEMENTAlthough the Smad4 protein has been suggested to act as a common Smad in the transforming growth factor-β (TGF-ß) superfamily signaling pathway in human embryonic stem cells, it has been unclear whether Smad4 has a noncanonical role in adipo-osteogenic differentiation of mesenchymal stem cells (MSCs), independent of the TGF-ß and bone morphogenic protein pathways. The study demonstrated that Smad4 plays a crucial role in the regulation of lineage commitment of the MSCs, including human adipose tissue-derived stem cells, into osteoblasts and adipocytes through modulating the retention of Taz in the nucleus during MSC differentiation. The Smad4 is specific to Taz but not YAP. Therefore, the findings provide new insight into a novel mechanism of the Smad4-Taz axis in adipo-osteogenic differentiation of MSCs and demonstrate a reciprocal role of Smad4 as a positive and negative factor in osteogenesis and adipogenesis of MSCs, respectively.

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“…In order to investigate if this is also true for human adipogenesis, we overexpressed miR125b-5p in preadipocytes and analyzed the global mRNA expression via Illumina BeadChip Microarray. However, Smad4 was not downregulated, indicating that it is no direct target of miR125b-5p during human adipogenesis 38 . Nonetheless, we identified CCAAT/enhancer-binding protein β (CEBPB), CCAAT/enhancer-binding protein delta (CEBPD) , and early B-cell factor 1 EBF1 as significantly downregulated (data not shown) after miR125b-5p overexpression.…”

Section: Discussionmentioning

confidence: 87%

Regulation of human adipogenesis by miR125b-5p

et al. 2016

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MicroRNAs (miRNAs) are non-coding RNAs that regulate target gene expression at the post-transcriptional level and are supposed to be implicated in the control of adipogenesis. We aimed to identify miRNAs which are involved in the regulation of human adipogenesis and searched for their molecular targets.Applying microarray-analysis we identified miR125b-5p as upregulated during human adipocyte differentiation, although its role during adipogenesis is unknown. We identified and characterized the matrix metalloproteinase 11 (MMP11) as a direct target of miR125b-5p by showing that miR125b-5p overexpression significantly reduces MMP11 luciferase activity and mutation of any single binding site was sufficient to abolish the miR125b-5p mediated inhibition of luciferase activity. MMP11 overexpression decreased fat accumulation, indicating that MMP11 acts as an anti-adipogenic regulator. In contrast, overexpression of miR125b-5p itself reduced adipogenesis.In summary, we identified miR125b-5p as upregulated during human adipogenesis indicating that miR125b-5p may serve as a regulator of human adipocyte differentiation. We further show that miR125b-5p downregulates the anti-adipogenic MMP11, but directly inhibits adipogenesis itself. Taken together, these data implicate that miR125b-5p can affect human adipogenesis via MMP11 and probably additional targets.

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MicroRNA-125b-5p inhibits proliferation and promotes adipogenic differentiation in 3T3-L1 preadipocytes

Cited by 31 publications

References 43 publications

MiR‐144‐3p regulates osteogenic differentiation and proliferation of murine mesenchymal stem cells by specifically targeting Smad4

MiR‐144‐3p regulates osteogenic differentiation and proliferation of murine mesenchymal stem cells by specifically targeting Smad4

A Reciprocal Role of the Smad4-Taz Axis in Osteogenesis and Adipogenesis of Mesenchymal Stem Cells

Regulation of human adipogenesis by miR125b-5p

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