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

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. 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.

Integration of genome‐wide association study and expression quantitative trait loci data identifies AIM2 as a risk gene of periodontitis

“…In addition, genes co‐expressed with AIM2 correlate with a number of pathways, including neutrophil activation, leucocyte migration, T‐cell activation, regulation of lymphocyte activation, and lymphocyte differentiation, according to GO analysis, and protein processing in endoplasmic reticulum, chemokine signalling pathway, and osteoclast differentiation in KEGG analysis. Considering the close association between immune inflammation and periodontitis (Bunte & Beikler, ), and the correlation between protein processing in the endoplasmic reticulum and periodontitis (P. Xue et al, ), the results of GO enrichment and KEGG analysis further support a potential role of AIM2 in the pathogenesis of periodontitis.…”

Low-intensity pulsed ultrasound upregulates osteogenesis under inflammatory conditions in periodontal ligament stem cells through unfolded protein response

“…However, the inflammatory state of the cells inhibits their osteogenic differentiation potential [10], impeding the repair and reconstruction of periodontal tissues. Xue et al reported that P-PDLSCs are in an endoplasmic reticulum stress (ERS) state [11], which is a pathological condition that induced the unfolded protein reaction (UPR) in cells to defend against the threat of ER Ca 2+ depletion, metabolic stimuli, defective glycosylation, energy deprivation, altered redox status, increased protein secretion, and inflammatory stimuli [12]. Hisanori et al reported a significant increase in the expression of UPRrelated genes in periodontitis [13].…”

“…Hisanori et al reported a significant increase in the expression of UPRrelated genes in periodontitis [13]. The prolonged inflammation of chronic periodontitis triggers UPR, leading to decreased osteogenic differentiation, whereas Xue et al reported that reducing ERS in a rat alveolar bone defect model increased the osteogenic capacity of P-PDLSCs [11]. In addition, Yamada et al found that ERS stimulated by P. gingivalis in experimental periodontitis in mice was involved in the alveolar bone resorption process [14].…”

Activation of autophagy in periodontal ligament mesenchymal stem cells promotes angiogenesis in periodontitis

“…PDLSCs’ biological function may be altered in inflammatory environment. For example, the osteogenesis ability of PDLSCs from inflamed ligament tissue was attenuated both in vivo and for several passages in vitro . PDLSCs autophagy can also be influenced by inflammation .…”

“…For example, the osteogenesis ability of PDLSCs from inflamed ligament tissue was attenuated both in vivo and for several passages in vitro. [15][16][17][18][19] PDLSCs autophagy can also be influenced by inflammation. 20 Autophagy can regulate MSCs secretory function in certain conditions.…”