Endoplasmic reticulum stress response mediated by the PERK-eIF2(alpha)-ATF4 pathway is involved in osteoblast differentiation induced by BMP2.
Endoplasmic reticulum stress response mediated by the PERK-eIF2(alpha)-ATF4 pathway is involved in osteoblast differentiation induced by BMP2.
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DOI：
10.1074/jbc.m110.152900
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发表时间：
2011-02-11
期刊：
影响因子：
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通讯作者：
Imaizumi K
中科院分区：
文献类型：
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作者：
Saito A;Ochiai K;Kondo S;Tsumagari K;Murakami T;Cavener DR;Imaizumi K
为了避免未折叠蛋白在内质网（ER）中的过量积累，真核细胞具有从ER到胞质溶胶或细胞核的信号传导途径。这些过程统称为ER应激反应。双链RNA激活蛋白激酶（PKR）样内质网激酶（PERK）是内质网应激反应的主要转导子，直接磷酸化eIF 2 α，导致翻译减弱。磷酸化eIF 2 α特异性促进转录因子ATF 4的翻译。ATF 4在成骨细胞分化和骨形成中起重要作用。据报道，Perk−/−小鼠表现出严重的骨质减少，在骨组织中观察到的表型与Atf 4 −/−小鼠非常相似。然而，PERK-eIF 2 α-ATF 4信号通路在骨生成中的参与尚不清楚。Perk−/−颅骨中磷酸化eIF 2 α和ATF 4蛋白水平减弱，ATF 4靶点骨钙素（Ocn）和骨唾液蛋白（Bsp）的基因表达水平也下调。用成骨细胞分化所需的BMP 2处理野生型原代成骨细胞，诱导ER应激，导致ATF 4蛋白表达水平增加。相反，Perk−/−成骨细胞中的ATF 4水平严重降低。结果表明，PERK信号传导是成骨细胞分化过程中ATF 4激活所必需的。Perk−/−成骨细胞表现出碱性磷酸酶活性下降，矿化结节形成相对于野生型文化延迟。通过将ATF 4引入Perk−/−成骨细胞，这些异常几乎完全恢复。总之，ER应激发生在成骨细胞分化期间，并激活PERK-eIF 2 α-ATF 4信号通路，随后促进骨生成所必需的基因表达，如Ocn和Bsp。
To avoid excess accumulation of unfolded proteins in the endoplasmic reticulum (ER), eukaryotic cells have signaling pathways from the ER to the cytosol or nucleus. These processes are collectively termed the ER stress response. Double stranded RNA activated protein kinase (PKR)-like endoplasmic reticulum kinase (PERK) is a major transducer of the ER stress response and directly phosphorylates eIF2α, resulting in translational attenuation. Phosphorylated eIF2α specifically promotes the translation of the transcription factor ATF4. ATF4 plays important roles in osteoblast differentiation and bone formation. Perk−/− mice are reported to exhibit severe osteopenia, and the phenotypes observed in bone tissues are very similar to those of Atf4−/− mice. However, the involvement of the PERK-eIF2α-ATF4 signaling pathway in osteogenesis is unclear. Phosphorylated eIF2α and ATF4 protein levels were attenuated in Perk−/− calvariae, and the gene expression levels of osteocalcin (Ocn) and bone sialoprotein (Bsp), which are targets for ATF4, were also down-regulated. Treatment of wild-type primary osteoblasts with BMP2, which is required for osteoblast differentiation, induced ER stress, leading to an increase in ATF4 protein expression levels. In contrast, the level of ATF4 in Perk−/− osteoblasts was severely diminished. The results indicate that PERK signaling is required for ATF4 activation during osteoblast differentiation. Perk−/− osteoblasts exhibited decreased alkaline phosphatase activities and delayed mineralized nodule formation relative to wild-type cultures. These abnormalities were almost completely restored by the introduction of ATF4 into Perk−/− osteoblasts. Taken together, ER stress occurs during osteoblast differentiation and activates the PERK-eIF2α-ATF4 signaling pathway followed by the promotion of gene expression essential for osteogenesis, such as Ocn and Bsp.