Dysregulation of the miR-146a-Smad4 axis impairs osteogenesis of bone mesenchymal stem cells under inflammation

Zheng, Liwei; Xu, Xin; Lin, Yao; Lin, Jiong; Wu, Jiahua; Tan, Jiali

doi:10.1038/boneres.2017.37

Cited by 41 publications

(25 citation statements)

References 29 publications

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“…Of note, we did not detect major differences of in vitro generated osteoclasts or osteoblasts, which contrast some published reports (Kuang et al, 2017). However, these data were primarily obtained upon manipulation of wt osteoblasts with antagomirs or miR‐146a agonists, while our analyses were done ex vivo with osteoblasts of wt and miR‐146a‐deficient mice, possibly explaining the difference outcomes.…”

Section: Discussioncontrasting

confidence: 99%

microRNA‐146a controls age‐related bone loss

et al. 2020

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Section: Discussioncontrasting

confidence: 99%

microRNA‐146a controls age‐related bone loss

et al. 2020

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“…D). To support this statistical analysis, we analyzed another public microRNA array data set (GS74299) , investigating the inverse relationship of Smad4 to miR‐146a expression . miR‐146a was significantly increased in osteoporetic bones compared to healthy ones (Supporting Information Fig.…”

Section: Resultsmentioning

confidence: 99%

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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“…Moreover, miR-146a is reportedly involved in high-glucose-induced endothelial inflammation, which suggests that it may be a novel therapeutic target for diabetic vascular disease ( 25 ). Overexpression of miR-146a inhibits osteogenesis by MSCs ( 32 ). In this study, AGEs-BSA had the opposite effects on miR-146a expression in VSMCs and MSCs, possibly explaining its opposite effects on osteogenesis of these cells.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the potential anti-inflammatory effect of miR-146a has widely been reports by the previous studies, Wei et.al reported that, miR-146a inhibits osteoblast proliferation and differentiation that results in the development of osteoporosis ( 32 ). On the other hand, the “off-target” or undesirable side effects such as osteoporosis and Vitamin D deficiency, maybe a major obstacle for future research.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, its overexpression of has protective effects in diabetic mellitus ( 20 , 30 , 31 ), suggest that miR-146a may serve as an important protector in diabetic condition. Despite the positive effect of miR-146a under diabetic condition, however, some studies suggested that miR-146a has a negative effect on MSC osteogenic differentiation ( 32 ). Interestingly, both AGEs-BSA and miR-146a play negative effects on MSC osteogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Exosomes Derived From Mesenchymal Stromal Cells Pretreated With Advanced Glycation End Product-Bovine Serum Albumin Inhibit Calcification of Vascular Smooth Muscle Cells

Wang

Zhu

et al. 2018

Front. Endocrinol.

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Background: The osteogenic differentiation of vascular smooth muscle cell (VSMCs) is important for the development of vascular calcification (VC), particularly in diabetes. Exosomes derived from Mesenchymal Stromal Cells (MSCs) are effective against cardiovascular diseases, yet their role in VC remains unclear. Advanced glycation end products (AGEs) inhibit bone marrow stromal cell osteogenesis by targeting osteogenesis-associated genes. Thus, we investigated the role of exosomes derived from MSCs pretreated with AGEs-BSA in VC and its potential mechanisms.Methods: Primary VSMCs and MSCs were isolated from the aorta and bone marrow of Sprague-Dawley rats, respectively. VSMCs were cultured with AGEs-BSA to induce osteogenic differentiation. Exosomes were harvested from MSCs by ultracentrifugation. MSCs and VSMCs were cocultured in Transwells, and exosomes were added to VSMC culture medium to assess their effects on osteogenic differentiation. Double luciferase reporter assay was applied to confirm that miR-146a directly targets the 3' UTR of the thioredoxin-interacting protein (TXNIP) gene.Results: Pretreatment of VSMCs with AGEs-BSA increased the expression of thioredoxin-interacting protein (TXNIP) by inhibiting that of miR-146a, resulting in enhanced ROS production and VSMC calcification. By contrast, the expression of miR-146a in MSCs was increased by AGEs-BSA treatment. Thus, miR-146a was transferred from AGEs-BSA-pretreated or miR-146a-transfected MSCs to VSMCs via exosomes. After coculture with miR-146a-containing exosomes, the AGEs-BSA-mediated increase in VSMC calcification was diminished, accompanied by decreased TXNIP expression and ROS production. Furthermore, TXNIP overexpression counteracted the anti-calcification effects of MSC-derived miR-146a-containing exosomes. In addition, TXNIP was identified as a target gene of miR-146a, and the results of double luciferase reporter assay confirmed that TXNIP was the direct target gene of miR-146a.Conclusions: Exosomes secreted by MSCs pretreated with AGEs-BSA contained a high level of miR-146a, which was transferred to VSMCs and inhibited AGEs-BSA-induced calcification in a TXNIP-dependent manner. Thus, miR-146a-containing exosomes may be a potential therapeutic target for VC.

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Dysregulation of the miR-146a-Smad4 axis impairs osteogenesis of bone mesenchymal stem cells under inflammation

Cited by 41 publications

References 29 publications

microRNA‐146a controls age‐related bone loss

microRNA‐146a controls age‐related bone loss

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

Exosomes Derived From Mesenchymal Stromal Cells Pretreated With Advanced Glycation End Product-Bovine Serum Albumin Inhibit Calcification of Vascular Smooth Muscle Cells

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