Notch signaling pathway promotes osteogenic differentiation of mesenchymal stem cells by enhancing BMP9/Smad signaling

Cao, Junjie; Wei, Yalin; Lian, Jingyao; Yang, Lunyun; Zhang, Xiaoyan; Xie, Junxia; Liu, Qiang; Luo, Jinyong; He, Bai‐Cheng; Tang, Min

doi:10.3892/ijmm.2017.3037

Cited by 71 publications

(74 citation statements)

References 56 publications

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“…Collected tissue samples were fixed in 10% buffered formalin overnight and embedded in paraffin. Serial sections were stained with hematoxylin and eosin (H&E, Sigma-Aldrich), Masson’s trichrome (Sigma-Aldrich), and alcian blue (Sigma-Aldrich) [17,27,38,53].…”

Section: Methodsmentioning

confidence: 99%

“…BMP9, also known as growth differentiation factor 2 (GDF-2)[25], was originally isolated from the fetal mouse liver [25,26]. Bone formation involves BMP9 acting through the Notch signaling pathway [14,24,27]. Several metabolic processes are regulated by BMP9, including glucose and lipid metabolism [28,29], iron metabolism [30], endothelial function, and angiogenesis [31,32,33].…”

Section: Introductionmentioning

confidence: 99%

“…We analyzed how GC-1spg cells react to BMP9 and demonstrate that BMP9 can induce bone formation in GC-1spg cells both in vitro and in vivo [10,17,38]. In addition, we analyzed the GC-1spg cell transcriptome after BMP9 treatment [27] and investigated potential BMP9 signaling pathways by KEGG enrichment analysis.…”

Section: Introductionmentioning

confidence: 99%

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Bone morphogenetic protein 9 induces osteogenic differentiation of germ cell 1 spermatogonial cells

Zhang

Xu²,

Chen³

et al. 2019

Preprint

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30Germ cell 1 spermatogonial (GC-1spg) cells are multipotent progenitor cells. We 31 previously confirmed that bone morphogenetic protein (BMP) 9 is among the most 32 osteogenic BMPs. However, whether GC-1spg cells are driven toward osteogenic 33 differentiation under proper stimuli is uncertain. Additionally, the molecular 34 mechanism of BMP9 remains unclear. In the present study, we aimed to determine 35 whether BMP9 can induce osteogenic differentiation of GC-1spg cells. Recombinant 36 adenoviruses were generated by the AdEasy system to regulate the BMP9 expression in 37 GC-1spg cells. We identified osteogenic markers by real-time PCR and staining 38 techniques in vitro. Ectopic ossification assays and histological analysis were also 39 performed to verify the in vivo activity of BMP9. Finally, potential signaling pathways 40 of BMP9 were assessed by transcriptome sequencing and KEGG enrichment analysis. 41Using recombinant adenoviruses, we demonstrate that BMP9 upregulates osteogenic 42 markers including Runx2, osteocalcin, osteopontin, and Sox9. BMP9 also activates 43 alkaline phosphatase activity and calcium deposition in GC-1spg cells. In vivo results 44show that BMP9 overexpression in GC-1spg cells promotes ectopic bone formation and 45 chondrogenesis. In addition, RNA-sequencing and KEGG pathway analysis 3 46 demonstrate that several signaling pathways are involved in BMP9-mediated 47 osteogenesis. GC-1spg cells not only maintain spermatogenesis but also retain the 48 ability to form bone tissue. Therefore, BMP9 activity in GC-1spg cells may help 49 identify signaling pathways implicated in bone formation and could be of use in 50 regenerative medicine. 51 Keywords: Bone morphogenetic protein 9, RNA-seq, KEGG pathway analysis, 52 recombinant adenovirus, chondrogenesis 53 Introduction 54 Germ cell 1 spermatogonial (GC-1spg) cells are mouse spermatogonia that are 55 immortalized by the SV40 large T antigen [1]. These cells can differentiate into diverse cell 56 types or undergo self-renewal, depending on different factors [2,3,4]. GC-1spg cells are 57 largely involved in spermatogenesis and have mesenchymal stem cell (MSC) differentiation 58 potential [5,6,7,8]. In other words, GC-1spg cells can differentiate into different cell types, 59including those of the osteogenic, chondrogenic, or adipogenic lineages [9,10,11,12]. 60However, several molecular events [13,14] and factors are involved in osteogenic 61 differentiation of MSCs. Importantly, bone morphogenetic proteins (BMPs) are essential for 62 this process [15,16,17]. 63 BMPs, members of the TGF-β superfamily, are required for bone formation, stem cell 64 differentiation, and male reproduction [15,16,18,19,20]. Thus far, more than 15 different 65 BMPs have been identified. Our previous work showed that BMP9 is the most osteogenic 66 BMP [21,22,23,24]. BMP9, also known as growth differentiation factor 2 (GDF-2)[25], was 67 originally isolated from the fetal mouse liver [25,26]. Bone formation involves BMP9 acting 68 through the Notch signaling ...

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Bone morphogenetic protein 9 induces osteogenic differentiation of germ cell 1 spermatogonial cells

Zhang

Xu²,

Chen³

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…BMMSCs are non-hematopoietic multipotent stem cells which can differentiate into adipogenic, osteogenic, and chondrogenic lineages (16, 17). These cells can secrete and respond to different signaling molecules and undergo osteogenic differentiation thereby playing an essential role in bone homeostasis (18, 25). Previous studies have shown that virus infection can affect functions of BMMSCs (21, 22, 26), but it is unclear whether BMMSCs are susceptible to alphavirus infection.…”

Section: Discussionmentioning

confidence: 99%

Chikungunya virus infection impairs osteogenic differentiation of bone marrow-derived mesenchymal stem cells

Roy

Shi

Duan

et al. 2019

Preprint

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20Chikungunya virus (CHIKV) is a positive-sense, single-stranded RNA virus, 21 belonging to the genus alphavirus in the family Togaviridae. The virus is spread by the 22 Importance 43Although studies have shown association of bone pathology and CHIKV 44 infection, the pathogenesis of infection causing altered bone homeostasis is not fully 45 understood. Here, we demonstrate for the first time that BMMSCs are susceptible to 46 CHIKV infection.Furthermore, we observe that infection causes disruption in the 47 function of BMMSC-derived osteogenic cells. Impaired function of these osteogenic 48 cells will likely lead to a disruption in bone homeostasis and in part, provides a 49 mechanism for the observed bone pathology associated with CHIKV pathogenesis. 50 Keywords 51 Chikungunya virus, mesenchymal stem cells, osteogenic differentiation 52 53 54 55 56 57 58 59 60 61 62 63

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“…Although many signals, such as Notch, Wnt/β‐catenin, and MAPKs, take part in osteogenic differentiation in MSCs. BMP/Smad signal is identified as the canonical pathway for BMPs …”

Section: Discussionmentioning

confidence: 99%

Inhibin α‐subunit inhibits BMP9‐induced osteogenic differentiation through blocking BMP/Smad signal and activating NF‐κB signal in mesenchymal stem cells

Huang

Cheng²,

Jitao³

et al. 2018

J of Cellular Biochemistry

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Inhibin-α, a member of the transforming growth factor (TGF-β) superfamily, has been involved in bone turnover during the menopausal transition via endocrine effects, and it was previously reported that inhibins may antagonize the function of BMPs. Certainly, one of the most important functions of BMPs is to induce osteogenic differentiation. BMP9 as one of the most potent BMPs to induce osteogenic differentiation has gotten more and more attentions. Nonetheless, the effects of inhibin-α on osteogenesis remain unknown. Besides, mesenchymal stem cells (MSCs) with the ability to differentiate into multiple mesenchymal lineages, including osteoblasts, adipocyte, chondrocytes, and myoblasts in vitro, have become the promising seed cells for bone tissue engineering. Here, we investigated the role of inhibin-α on BMP9-induced osteogenic differentiation in MSCs and tried to discover the mechanism underlying this process. We found inhibin-α apparently reduced the classical osteogenic markers and the ectopic bone formation induced by BMP9. In addition, the ratio of OPG to RANKL is declined also in the presence of inhibin-α. For mechanism, we found that exogenous expression of inhibin-α inhibits BMP9-induced osteogenic differentiation through blocking BMP/Smad signal transduction and activating NF-κB signal which is repressed by BMP9. Thus, our findings indicated that inhibin-α has a negative effect on BMP9-induced osteogenic differentiation in MSCs, which may provide a novel insight into the regulation of skeletal development and new strategy for bone tissue engineering.

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Notch signaling pathway promotes osteogenic differentiation of mesenchymal stem cells by enhancing BMP9/Smad signaling

Cited by 71 publications

References 56 publications

Bone morphogenetic protein 9 induces osteogenic differentiation of germ cell 1 spermatogonial cells

Bone morphogenetic protein 9 induces osteogenic differentiation of germ cell 1 spermatogonial cells

Chikungunya virus infection impairs osteogenic differentiation of bone marrow-derived mesenchymal stem cells

Inhibin α‐subunit inhibits BMP9‐induced osteogenic differentiation through blocking BMP/Smad signal and activating NF‐κB signal in mesenchymal stem cells

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