Abstract
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.
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Abbreviations
- ER:
-
endoplasmic reticulum
- UPR:
-
unfolded protein response
- MSCs:
-
mesenchymal stem cells
- KAT6B/MORF:
-
lysine acetyltransferase 6B
- PERK:
-
protein kinase RNA-like ER kinase
- IRE1:
-
inositol-requiring protein 1
- ATF6:
-
activating transcription factor 6
- HATs:
-
histone acetyltransferases
- P-MSCs:
-
MSCs from periodontitis patients
- H-MSCs:
-
MSCs from normal patients
- TEM:
-
transmission electron microscopy
- IL-1β:
-
interleukin-1 β
- TNF-α:
-
tumor necrosis factor α
- Runx2:
-
runt-related transcription factor 2
- OCN:
-
osteocalcin
- KAT2A:
-
lysine acetyltransferase 2A
- KAT6A:
-
lysine acetyltransferase 6A
- KAT3B:
-
lysine acetyltrans- ferase 3B
- ATF4:
-
activating transcription factor 4
- ChIP:
-
chromatin immunoprecipitation
- Tm:
-
tunicamycin
- Tg:
-
thapsigargin
- 4-PBA:
-
4-phenyl butyric acid
- CEJ:
-
the cemento-enamel junction
- ROS:
-
reactive oxygen species
- IFN-γ:
-
interferon-γ
- BMP2:
-
bone morphogenetic proteins
- ALP:
-
alkaline phosphatase
- RANKL:
-
receptor activator for nuclear factor-κ B ligand
- PE:
-
phycoerythrin
- FITC:
-
fluorescein isothiocynante
- SD rats:
-
Sprague-Dawley rats
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Acknowledgements
This work was supported by the grants from the National Natural Science Foundation of China (No. 81470710 to YJ, 81470742 to QTW, 31401255 to BL, 81271137 to QTW, 81570976 to FJ and 31301140 to XNH).
Author contributions
PX, BL and YA were involved in the practical achievement of the experiments. PX, BL, YA, XNH, JS and DF collected, analyzed and interpreted the data. PX and BL drafted the manuscript. GYD, RH and FJ provided human teeth samples for the experiments. YJ and QTW designed the study, wrote the manuscript and provided administrative support. All the authors read and approved the manuscript for publication.
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Xue, P., Li, B., An, Y. et al. Decreased MORF leads to prolonged endoplasmic reticulum stress in periodontitis-associated chronic inflammation. Cell Death Differ 23, 1862–1872 (2016). https://doi.org/10.1038/cdd.2016.74
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DOI: https://doi.org/10.1038/cdd.2016.74
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