ATF4在内质网应激调控成骨分化中的作用  

The Role of ATF4 in Endoplasmic Reticulum Stress in the Regulation of Osteogenic Differentiation

作　　者：黄媚 陈熙[2] 邹军[1] HUANG Mei;CHEN Xi;ZOU Jun(School of Kinesiology,Shanghai University of Sport,Shanghai 200438,China;School of Sports Science,Wenzhou Medical University,Wenzhou 325035,Zhejiang,China)

机构地区：[1]上海体育学院运动科学学院,上海200438 [2]温州医科大学体育科学学院,浙江温州325035

出　　处：《中国生物化学与分子生物学报》2020年第1期29-35,共7页Chinese Journal of Biochemistry and Molecular Biology

基　　金：国家自然科学基金(No.81702235,No.81871835)资助项目;上海市人类运动能力开发与保障重点实验室(上海体育学院)资助项目(No.11DZ2261100)~~

摘　　要：为避免内质网中未折叠蛋白质的过度累积,真核细胞能激活一系列信号通路来维持内质网稳态,这个过程称为内质网应激。在骨生长发育中,适宜的内质网应激有助于成骨细胞、破骨细胞和软骨细胞的生长,可以促进骨髓间充质干细胞向成骨细胞分化。而过度的内质网应激会抑制成骨分化,严重的甚至导致骨质疏松、成骨不全等相关骨病的发生。内质网应激时可激活未折叠蛋白质反应,其主要是通过PERK/eIF2α/ATF4信号通路,上调转录激活因子4(ATF4)的表达。ATF4位于许多成骨分化调节因子的下游,是促进成骨分化的关键因子,在内质网应激对成骨分化的调节中发挥重要作用。在成骨分化过程中,适宜的内质网应激能通过激活PERK信号通路,诱导ATF4表达增加,进而上调骨钙素、骨涎蛋白等成骨所必需基因的表达,促进成骨分化。过度的内质网应激会激活ATF4/CHOP促凋亡途径,并导致Bax、胱天蛋白酶等凋亡信号分子的大量产生,进而导致细胞凋亡,抑制成骨分化。由于ATF4在ERS和成骨分化中的重要作用,ATF4在骨质疏松、成骨不全等骨相关疾病的治疗中具有重要意义。本文通过综述ATF4在内质网应激调控成骨分化中的作用机制,为相关骨性疾病治疗提供理论依据。In order to avoid the excessive accumulation of unfolded proteins in endoplasmic reticulum,eukaryotic cells can activate a series of signaling pathways to restore the homeostasis of endoplasmic reticulum,which is endoplasmic reticulum stress. Appropriate endoplasmic reticulum stress can contribute to the growth of osteoblasts,osteoclasts and chondrocytes. It also promotes the differentiation of bone marrow mesenchymal stem cells into osteoblasts. While excessive endoplasmic reticulum stress can inhibit osteogenic differentiation,leading to osteoporosis,osteogenesis imperfecta and other related osteopathy.The endoplasmic reticulum stress activates the unfolded protein response,and up-regulates the expression of activating transcription factor 4( ATF4) mainly through the PERK/e IF2α/ATF4 signaling pathway. At the same time,ATF4 is located downstream of many osteogenic differentiation regulators,which is the key factor of osteogenic differentiation. ATF4 plays an important role in the regulation of osteogenic differentiation by endoplasmic reticulum stress. In the process of osteogenic differentiation,appropriate endoplasmic reticulum stress can induce the expression of ATF4 by activating the PERK signaling pathway,and then up-regulate the expression of osteogenic related genes such as osteocalcin and osteopontin,and promote osteogenic differentiation. Excessive endoplasmic reticulum stress activates the ATF4/CHOP pathway and leads to the production of apoptotic signaling molecules such as Bax and Caspase,which leads to apoptosis and inhibition of osteogenic differentiation. ATF4 is of great significance in the treatment of bone-related diseases such as osteoporosis and osteogenesis due to the important role of ATF4 in endoplasmic reticulum stress regulation of osteogenic differentiation. This article reviews the mechanism of endoplasmic stress in regulating osteogenic differentiation through ATF4,which provides a theoretical basis for the treatment of related bone diseases.

关 键 词：内质网应激 转录激活因子4(ATF4) 成骨分化 凋亡 

分 类 号：Q291[生物学—细胞生物学]