PERK-eIF2α-ATF4 pathway mediated by endoplasmic reticulum stress response is involved in osteodifferentiation of human periodontal ligament cells under cyclic mechanical force

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• 作者：Shuang-Yan Yang ; Fu-Lan Wei ; Li-Hua Hu ; Chun-Ling Wang ; ^{wangchl@sdu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：α-MEM ; alpha minimum essential medium ; ATF4 ; activating transcription factor 4 ; ATF6 ; activating transcription factor 6 ; BMP2 ; bone morphogenic protein 2 ; BSP ; bone sialoprotein ; CREB ; cAMP response element binding ; CMF ; cyclic mechanical force ; DM ; diabetes mellitus ; ECL ; enhanced chemiluminescence ; eIF2 ; eukaryotic initiation factor 2 ; eIF2α ; α-subunit of eukaryotic initiation factor 2 ; ENi· ; S ; enhanced infection solution ; ER ; endoplasmic reticulum ; ERS ; endoplasmic reticulum stress ; FBS
• 刊名：Cellular Signalling
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：28
• 期：8
• 页码：880-886
• 全文大小：1199 K

文摘

To prevent excess accumulation of unfolded proteins in endoplasmic reticulum (ER), eukaryotic cells have signaling pathways from the ER to the cytosol or nucleus. These processes are known as the endoplasmic reticulum stress (ERS) response. Protein kinase R like endoplasmic reticulum kinase (PERK) is a major transducer of the ERS response and it directly phosphorylate α-subunit of eukaryotic initiation factor 2 (eIF2α), resulting in translational attenuation. Phosphorylated eIF2α specifically promoted the translation of the activating transcription factor 4 (ATF4). ATF4 is a known important transcription factor which plays a pivotal role in osteoblast differentiation and bone formation. Furthermore, ATF4 is a downstream target of PERK. Studies have shown that PERK-eIF2α-ATF4 signal pathway mediated by ERS was involved in osteoblastic differentiation of osteoblasts. We have known that orthodontic tooth movement is a process of periodontal ligament cells (PDLCs) osteodifferentiation and alveolar bone remodeling under mechanical force. However, the involvement of PERK-eIF2α-ATF4 signal pathway mediated by ERS in osteogenic differentiation of PDLCs under mechanical force has not been unclear. In our study, we applied the cyclic mechanical force at 10% elongation with 0.5 Hz to mimic occlusal force, and explored whether PERK-eIF2α-ATF4 signaling pathway mediated by ERS involved in osteogenic differentiation of PDLCs under mechanical force. Firstly, cyclic mechanical force will induce ERS and intensify several osteoblast marker genes (ATF4, OCN, and BSP). Next, we found that PERK overexpression increased eIF2α phosphorylation and expression of ATF4, furthermore induced BSP, OCN expression, thus it will promote osteodifferentiation of hPDLCs; mechanical force could promote this effect. However, PERK^−/− cells showed the opposite changes, which will inhibit osteodifferentiation of hPDLCs. Taken together, our study proved that PERK-eIF2α-ATF4 signaling pathway mediated by ERS involved in osteoblast differentiation of PDLCs under cyclic mechanical force.