Differential regulation of osteoclastogenesis by Notch2/Delta-like 1 and Notch1/Jagged1 axes

Sekine, Chiyoko; Koyanagi, Akemi; Koyama, Noriko; Hozumi, Katsuto; Chiba, Shigeru; Yagita, Hideo

doi:10.1186/ar3758

Cited by 71 publications

(89 citation statements)

References 36 publications

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“…DLL3 is a spondylocostal dysplasia/pudgy gene whose mutation may lead to axial skeletal defects and spondylocostal dysostosis [26][27][28]. Similarly, DLL3 has been reported to be a candidate gene that has been implicated in vertebral malformations, while its binding to Notch represents a significant factor in somitogenesis, capable of promoting osteoclastogenesis through Notch2 [29,30]. A key finding of the present study provided evidence suggesting that it is reasonable to estimate that LINC00311 is upregulated in osteoporosis and that DLL3 is a factor affecting osteoporosis largely due to the increased expression levels of a great number of lncRNAs in orthopedic diseases, with many orthopedic diseases shown to be influenced by DLL3.…”

Section: Figure 14mentioning

confidence: 99%

LncRNA LINC00311 Promotes the Proliferation and Differentiation of Osteoclasts in Osteoporotic Rats Through the Notch Signaling Pathway by Targeting DLL3

Wang¹,

Luo²,

Liu³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Osteoporosis is a commonly occurring condition marked by a loss of bone density. Previous evidence has highlighted the roles played by microRNAs as potential treatment tools for the disease. At present, the influence of long non-coding RNAs (lncRNAs) on the progression of osteoporosis remains largely unclear. Thus, an investigation was conducted into the target relationship between LINC00311, which has been reported to be highly expressed in osteoporosis, and delta-like 3 (DLL3), which is involved in the Notch signaling pathway, in connection with a series of bioinformatic methods. An osteoporotic rat model was established by means of ovariectomy (OVX) to evaluate the influence exerted by DLL3-binding LINC00311 on osteoclasts through the Notch signaling pathway. Methods: Osteoclasts were extracted from osteoporotic rats and transfected with the LINC00311-vector, shRNA-LINC00311, Notch activator, or a combination of the Notch activator and LINC00311-vector. Western blotting and RT-qPCR techniques were applied to determine the expression levels of LINC00311, DLL3, Notch1, Notch2, Jagged1, Hes-1 and TRAP in tissues and cells, while cell activity was detected by MTT assay. The cell cycle as well as the rate of apoptosis was detected by flow cytometry. The successfully established osteoporotic rats were designated into the OVX-siRNA, OVX-LINC00311 and OVX-control groups to observe the effects of LINC00311 on the proliferation and differentiation of osteoclasts. Results: Cells transfected with the LINC00311-vector exhibited increased expression levels of Notch2 and TRPA as well as increased cell activity, while decreased expression levels of DLL3, Notch1, Jagged1 and Hes-1, along with a decreased cell apoptosis rate, were observed. The opposite tendencies of these parameters were observed in the cells treated with shRNA-LINC00311. A key observation was made when the Notch signaling pathway was activated, in that the cell activity was decreased while the rate of apoptosis increased. In comparison with the OVX-control group, the expression levels of LINC00311, Notch2 and TRAP as well as the positive expression rate of TRAP all exhibited reductions, while those of DLL3, Jagged1 and Notch1 were elevated in the OVX-siRNA group. Compared with those in the sham group, in the OVX-control and OVX-LINC00311 groups, LINC00311 and the expression levels of Notch2 and TRAP were increased; however, decreased levels of DLL3, Jagged1 and Notch1 were noted. Conclusions: Taken together, the key findings of the present study suggest that LINC00311 induces proliferation and inhibits apoptosis of osteoclasts via the regulation of the Notch signaling pathway by inhibiting DLL3 expression, ultimately demonstrating that LINC00311 and its target gene DLL3 may serve as independent factors in cases of osteoporosis.

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Section: Figure 14mentioning

confidence: 99%

LncRNA LINC00311 Promotes the Proliferation and Differentiation of Osteoclasts in Osteoporotic Rats Through the Notch Signaling Pathway by Targeting DLL3

Wang¹,

Luo²,

Liu³

et al. 2018

Cell Physiol Biochem

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“…The hybridoma cells were prepared as described above, and antibodies that reacted with mouse Notch2-transfected CHO cells, but not with untransfected CHO cells, were screened and cloned. All these mAbs were purified from ascites produced in pristan-primed ICR nude mice by the caprylic acid and ammonium sulphate precipitation method [36][37][38][39] . Two hundred and fifty micrograms of HMJ1-29 or control hamster IgG (UC8-1B9) and 100 mg of HMN1-12 or HMN2-29 were injected intraperitoneally on the indicated days.…”

Section: Methodsmentioning

confidence: 99%

Notch2 activation ameliorates nephrosis

et al. 2014

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“…NOTCH mediates hypoxia-induced angiogenesis in RA by increasing the function of microvascular endothelial cells (47). Recent studies using DAPT (48) or an anti-mouse Deltalike 1-blocking monoclonal antibody (49) reported that NOTCH inhibition in mice with inflammatory arthritis reduces the severity of inflammation and inhibits osteoclastogenesis. These reports highlight the complexity of NOTCH signaling under normal and pathological conditions.…”

Section: Figurementioning

confidence: 99%

NOTCH inhibits osteoblast formation in inflammatory arthritis via noncanonical NF-κB

Zhang¹,

Hilton²,

Anolik³

et al. 2014

J. Clin. Invest.

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NOTCH-dependent signaling pathways are critical for normal bone remodeling; however, it is unclear if dysfunctional NOTCH activation contributes to inflammation-mediated bone loss, as observed in rheumatoid arthritis (RA) patients. We performed RNA sequencing and pathway analyses in mesenchymal stem cells (MSCs) isolated from transgenic TNF-expressing mice, a model of RA, to identify pathways responsible for decreased osteoblast differentiation. 53 pathways were dysregulated in MSCs from RA mice, among which expression of genes encoding NOTCH pathway members and members of the noncanonical NF-κB pathway were markedly elevated. Administration of NOTCH inhibitors to RA mice prevented bone loss and osteoblast inhibition, and CFU-fibroblasts from RA mice treated with NOTCH inhibitors formed more new bone in recipient mice with tibial defects. Overexpression of the noncanonical NF-κB subunit p52 and RELB in a murine pluripotent stem cell line increased NOTCH intracellular domain-dependent (NICD-dependent) activation of an RBPjκ reporter and levels of the transcription factor HES1. TNF promoted p52/RELB binding to NICD, which enhanced binding at the RBPjκ site within the Hes1 promoter. Furthermore, MSC-enriched cells from RA patients exhibited elevated levels of HES1, p52, and RELB. Together, these data indicate that persistent NOTCH activation in MSCs contributes to decreased osteoblast differentiation associated with RA and suggest that NOTCH inhibitors could prevent inflammation-mediated bone loss. IntroductionPatients with chronic inflammatory diseases, such as rheumatoid arthritis (RA), often have severe systemic bone loss and increased risk of fracture due to increased bone resorption and decreased bone formation, partially mediated by elevated TNF levels (1). We (1-4) and others (5, 6) have reported that TNF inhibits bone formation by affecting major osteoblast regulatory pathways, including BMP/SMAD/RUNX2 and WNT-β-catenin, but the role of TNF in osteoblast differentiation from MSCs has not been fully defined. The TNF transgenic (TNF-Tg) mouse model we use, line 3647, represents a good model of RA to study the influence of chronically elevated, but relatively low, levels of TNF and TNF-induced inflammation on bone cell function and MSC differentiation into osteoblasts (7). To attempt to identify molecules responsible for reduced differentiation of MSCs into osteoblasts in RA, we performed genome-wide screening and pathway analyses using data from RNA sequencing (RNA-Seq) of MSCs purified from TNF-Tg mice and WT littermates. We found that genes in the NOTCH and noncanonical NF-κB signaling pathways were markedly upregulated in TNF-Tg mouse MSCs, raising the possibility that NOTCH may interact with noncanonical NF-κB proteins in MSCs to inhibit their osteogenic differentiation.NOTCH is a family of evolutionarily conserved receptors that regulate cell fate. NOTCH receptors are activated following direct contact with their ligands expressed on adjacent cells. In mammals, there are 4 NOTCH receptors (NOTCH1-NOTCH4)...

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Differential regulation of osteoclastogenesis by Notch2/Delta-like 1 and Notch1/Jagged1 axes

Cited by 71 publications

References 36 publications

LncRNA LINC00311 Promotes the Proliferation and Differentiation of Osteoclasts in Osteoporotic Rats Through the Notch Signaling Pathway by Targeting DLL3

LncRNA LINC00311 Promotes the Proliferation and Differentiation of Osteoclasts in Osteoporotic Rats Through the Notch Signaling Pathway by Targeting DLL3

Notch2 activation ameliorates nephrosis

NOTCH inhibits osteoblast formation in inflammatory arthritis via noncanonical NF-κB

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