Xue Peng, Li Bei, An Ying, Sun Jin, He Xiaoning, Hou Rui, Dong Guangying, Fei Dongdong, Jin Fang, Wang Qintao, Jin Yan
State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Disease, Department of Periodontology, School of Stomatology, The Fourth Military Medical University, Shaanxi Key Laboratory of Stomatology, Xi'an, Shaanxi 710032, China.
State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Disease, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
Cell Death Differ. 2016 Nov 1;23(11):1862-1872. doi: 10.1038/cdd.2016.74. Epub 2016 Jul 22.
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.
炎症与内质网（ER）应激之间的关联已在多种疾病中有所描述。然而，慢性炎症是否以及如何调控未折叠蛋白反应（UPR）并促进慢性炎症性疾病的内质网稳态仍不清楚。在本研究中，慢性炎症在牙周炎背景下导致间充质干细胞内质网应激。长期促炎细胞因子诱导内质网应激延长，并降低牙周膜干细胞（PDLSCs）的成骨分化能力。有趣的是，我们发现慢性炎症会降低组蛋白乙酰转移酶赖氨酸乙酰转移酶6B（KAT6B，也称为MORF）的表达，并导致关键UPR传感器PERK的上调，从而导致PDLSCs中UPR的持续激活。此外，我们发现慢性炎症中介导的MORF激活的UPR在体内和体外均导致PDLSCs成骨分化的PERK相关恶化。综上所述，我们的结果表明，慢性炎症通过MORF介导的PERK转录损害UPR功能，这是一种先前未被认识的机制，导致牙周炎中内质网功能受损、内质网应激延长和PDLSCs成骨分化缺陷。
