ER stress-inducible ATF3 suppresses BMP2-induced ALP expression and activation in MC3T3-E1 cells

Park, Jae-kyung; Jang, Hoon; Hwang, Seongsoo; Kim, Eun-Jung; Kim, Dong-Ern; Oh, Keon-Bong; Kwon, Deok-Ho; Koh, Jeong‐Tae; Kimura, Kumi; Inoue, Hiroshi; Jang, Won‐Gu; Lee, Jeong-Woong

doi:10.1016/j.bbrc.2013.11.121

Cited by 25 publications

(18 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…18 However, in OS732 cells, fluoride-induced osteoblastic and osteoclastic differentiation was due to the activation of ALP and receptor activator for nuclear factor-κB ligand (RANKL) mediated by the PERK pathway, but had no effect on Runx2 and osteoprotegerin. 19 The alcohol-induced ER stress inhibited the osteogenesis of MSCs by suppressing the Wnt/β-catenin pathway, downregulating the Osf2/Cbfa1 gene, and activating TNF-α signaling by the PERK/ATF4/CHOP pathway.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Decreased MORF leads to prolonged endoplasmic reticulum stress in periodontitis-associated chronic inflammation

Xue

et al. 2016

Cell Death Differ

View full text Add to dashboard Cite

The association between inflammation and endoplasmic reticulum (ER) stress has been described in many diseases. However, if and how chronic inflammation governs the unfolded protein response (UPR) and promotes ER homeostasis of chronic inflammatory disease remains elusive. In this study, chronic inflammation resulted in ER stress in mesenchymal stem cells in the setting of periodontitis. Long-term proinflammatory cytokines induced prolonged ER stress and decreased the osteogenic differentiation of periodontal ligament stem cells (PDLSCs). Interestingly, we showed that chronic inflammation decreases the expression of lysine acetyltransferase 6B (KAT6B, also called MORF), a histone acetyltransferase, and causes the upregulation of a key UPR sensor, PERK, which lead to the persistent activation of the UPR in PDLSCs. Furthermore, we found that the activation of UPR mediated by MORF in chronic inflammation contributes to the PERK-related deterioration of the osteogenic differentiation of PDLSCs both in vivo and in vitro. Taken together, our results suggest that chronic inflammation compromises UPR function through MORF-mediated-PERK transcription, which is a previously unrecognized mechanism that contributes to impaired ER function, prolonged ER stress and defective osteogenic differentiation of PDLSCs in periodontitis. Cell Death and Differentiation (2016) 23, 1862-1872 doi:10.1038/cdd.2016; published online 22 July 2016The endoplasmic reticulum (ER) primarily functions in protein biosynthesis and folding, lipid trafficking, metabolism and intracellular calcium storage. Elevated physiological demand for protein folding can cause the accumulation of misfolded or unfolded proteins in the ER lumen, a state called ER stress.

show abstract

Section: Discussionmentioning

confidence: 99%

“…[12][13][14] Controversial evidence was found in the regulation of the osteogenic differentiation of MSCs by 1 UPR activation. [15][16][17][18][19][20] However, how ER stress results in the abnormal differentiation of PDLSCs remains largely unknown.…”

mentioning

confidence: 99%

Decreased MORF leads to prolonged endoplasmic reticulum stress in periodontitis-associated chronic inflammation

Xue

et al. 2016

Cell Death Differ

View full text Add to dashboard Cite

show abstract

“…Our results revealed that cyclic stretch of 10% elongation or treatment with BMP-2 at a concentration of 200 ng/ml exhibited the most obvious effects on osteoblastic differentiation markers (ALP and Runx2). Moreover, previous in vitro studies have also used similar magnitudes of mechanical stretch to investigate the mechanotransduction of bone cells ( 31 , 32 ) and the same concentrations of BMP-2 have been applied to research osteoblastic differentiation ( 5 , 33 ). Furthermore, our findings also demonstrated that treatment with BMP-2 at a lower concentration (50 ng/ml) induced an increase in ALP mRNA levels, but not in ALP activity in the medium.…”

Section: Discussionmentioning

confidence: 99%

“…Runx2, a bone-specific transcription factor, plays an essential role in bone formation in vivo and osteoblastic differentiation in vitro ( 34 , 35 ). Runx2 forms a heterodimeric complex with the transcriptional co-activator core binding factor β, and binds to osteoblast-specific cis -element 2 sites to modulate the transcription of osteoblast-related genes ( 34 , 36 ), such as ALP, an early-stage marker of osteoblastic differentiation ( 33 ). Therefore, in this study, we investigated the synergistic effects of cyclic stretch and BMP-2 on ALP and Runx2 expression to demonstrate osteogenic differentiation.…”

Section: Discussionmentioning

confidence: 99%

Cyclic stretch enhances bone morphogenetic protein-2-induced osteoblastic differentiation through the inhibition of Hey1

Zeng

Yin

Zhang

et al. 2015

International Journal of Molecular Medicine

View full text Add to dashboard Cite

Substantial evidence has indicated that osteoblastic differentiation may be regulated by mechanical loads or bone morphogenetic protein-2 (BMP-2). BMP-2-induced in vivo osteogenesis can be significantly enhanced in the presence of mechanical stimuli, revealing the therapeutic potential of the combined application of BMP-2 and mechanical loads in clinical bone diseases (e.g., bone fractures and osteoporosis); however, the underlying mechanisms remain elusive. In this study, we found that cyclic stretch or BMP-2 alone increased the expression of osteoblastic differentiation markers, including alkaline phosphatase (ALP) and runt-related transcription factor 2 (Runx2), as shown by RT-qPCR, western blot analysis and ALP activity test. Furthermore, our results revealed that cyclic mechanical stretch with 10% elongation at 0.1 Hz significantly enhanced the BMP-2-induced upregulation of ALP and Runx2 expression in osteoblast-like MC3T3-E1 cells. Cyclic stretch also inhibited the BMP-2-induced upregulation of Hes-related family bHLH transcription factor with YRPW motif 1 (Hey1, measured by RT-qPCR and immunofluorescence staining), a potent negative regulator of osteogenesis. Moreover, the transient transfection of a Hey1 expression plasmid (pcDNA3.1-Hey1) significantly reversed the effects of cyclic stretch on the BMP-2-induced upregulation of differentiation markers in the MC3T3-E1 cells. This revealed the importance of Hey1 in modulating BMP-2-induced osteoblastic differentiation in response to cyclic stretch. Taken together, our results demonstrated that cyclic stretch enhanced the BMP-2-induced osteoblastic differentiation through the inhibition of Hey1. The present study broadens our fundamental knowledge of osteoblastic mechanotransduction and also sheds new insight into the mechanisms through which the combined application of BMP-2 and mechanical load promotes osteogenesis.

show abstract

“…AMP‐dependent transcription factor‐3 (ATF‐3) is a member of the ATF/cAMP response binding‐protein (CREB) family of transcription factors, which suppress ALP expression and activation, and therefore regulate osteogenic differentiation. It is generally accepted that BMP‐2 reduces ATF‐3 protein expression, and overexpression of ATF‐3 negatively regulated BMP‐2‐induced ALP expression (Park et al , ). In line with such evidence in porcine ASCs, treated with BMP‐2, ATF‐3 is also downregulated.…”

Section: Discussionmentioning

confidence: 99%

Molecular- and microarray-based analysis of diversity among resting and osteogenically induced porcine mesenchymal stromal cells of several tissue origin

Bayraktar

Jungbluth

Deenen

et al. 2017

J Tissue Eng Regen Med

View full text Add to dashboard Cite

Mesenchymal stromal cells (MSCs) play a pivotal role in modern therapeutic approaches in bone‐healing disorders. Although bone marrow‐derived MSCs are most frequently used, the knowledge that many other adult tissues represent promising sources for potent MSCs has gained acceptance. In the present study, the osteogenic differentiation potential of porcine skin fibroblasts (FBs), as well as bone marrow‐ (BMSCs), adipose tissue‐ (ASCs) and dental pulp‐derived stromal cells (DSCs) were evaluated. However, additional application of BMP‐2 significantly elevated the delayed osteogenic differentiation capacity of ASC and FB cultures, and in DSC cultures the supplementation of platelet‐rich plasma increased osteogenic differentiation potential to a comparable level of the good differentiable BMSCs. Furthermore, microarray gene expression performed in an exemplary manner for ASCs and BMSCs revealed that ASCs and BMSCs use different gene expression patterns for osteogenic differentiation under standard media conditions, as diverse MSCs are imprinted dependent from their tissue niche. However, after increasing the differentiation potential of ASCs to a comparable level as shown in BMSCs, a small subset of identical key molecules was used to differentiate in the osteogenic lineage. Until now, the importance of identified genes seems to be underestimated for osteogenic differentiation. Apparently, the regulation of transmembrane protein 229A, interleukin‐33 and the fibroblast growth factor receptor‐2 in the early phase of osteogenic differentiation is needed for optimum results. Based on these results, bone regeneration strategies of MSCs have to be adjusted, and in vivo studies on the osteogenic capacities of the different types of MCSs are warranted. Copyright © 2016 The Authors Tissue Engineering and Regenerative Medicine published by John Wiley & Sons, Ltd.

show abstract

ER stress-inducible ATF3 suppresses BMP2-induced ALP expression and activation in MC3T3-E1 cells

Cited by 25 publications

References 38 publications

Decreased MORF leads to prolonged endoplasmic reticulum stress in periodontitis-associated chronic inflammation

Decreased MORF leads to prolonged endoplasmic reticulum stress in periodontitis-associated chronic inflammation

Cyclic stretch enhances bone morphogenetic protein-2-induced osteoblastic differentiation through the inhibition of Hey1

Molecular- and microarray-based analysis of diversity among resting and osteogenically induced porcine mesenchymal stromal cells of several tissue origin

Contact Info

Product

Resources

About