PERK-eIF2α-ATF4 pathway mediated by endoplasmic reticulum stress response is involved in osteodifferentiation of human periodontal ligament cells under cyclic mechanical force.
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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DOI：
10.1016/j.cellsig.2016.04.003
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发表时间：
2016-08
影响因子：
4.8
通讯作者：
Shuangyan Yang;Fu-lan Wei;Li-hua Hu;Chun-ling Wang
中科院分区：
文献类型：
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作者：
Shuangyan Yang;Fu-lan Wei;Li-hua Hu;Chun-ling Wang
为了防止未折叠蛋白在内质网 (ER) 中过度积累，真核细胞具有从 ER 到细胞质或细胞核的信号传导途径。这些过程称为内质网应激（ERS）反应。蛋白激酶 R 样内质网激酶 (PERK) 是 ERS 反应的主要转导因子，它直接磷酸化真核起始因子 2 (eIF2α) 的 α 亚基，导致翻译减弱。磷酸化 eIF2α 特异性促进激活转录因子 4 (ATF4) 的翻译。 ATF4是已知的重要转录因子，在成骨细胞分化和骨形成中发挥关键作用。此外，ATF4 是 PERK 的下游靶点。研究表明ERS介导的PERK-eIF2α-ATF4信号通路参与成骨细胞的成骨分化。我们知道，正畸牙齿移动是牙周膜细胞（PDLCs）在机械力作用下骨分化和牙槽骨重塑的过程。然而，ERS介导的PERK-eIF2α-ATF4信号通路在机械力作用下PDLCs成骨分化中的参与尚不清楚。在我们的研究中，我们应用 10% 伸长率、0.5 Hz 的循环机械力来模拟咬合力，并探讨 ERS 介导的 PERK-eIF2α-ATF4 信号通路是否参与机械力下 PDLC 的成骨分化。首先，循环机械力会诱导 ERS 并强化一些成骨细胞标记基因（ATF4、OCN 和 BSP）。接下来我们发现PERK过表达会增加eIF2α磷酸化和ATF4的表达，进而诱导BSP、OCN的表达，从而促进hPDLCs的骨分化；机械力可以促进这种效果。然而，PERK−/−细胞表现出相反的变化，这将抑制hPDLCs的骨分化。综上所述，我们的研究证明ERS介导的PERK-eIF2α-ATF4信号通路参与循环机械力下PDLCs的成骨细胞分化。
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.