Advanced glycation end products suppress osteoblastic differentiation of stromal cells by activating endoplasmic reticulum stress.
Advanced glycation end products suppress osteoblastic differentiation of stromal cells by activating endoplasmic reticulum stress.
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DOI：
10.1016/j.bbrc.2013.07.126
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发表时间：
2013-08
影响因子：
3.1
通讯作者：
Ken-ichiro Tanaka;Toru Yamaguchi;H. Kaji;I. Kanazawa;T. Sugimoto
中科院分区：
文献类型：
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作者：
Ken-ichiro Tanaka;Toru Yamaguchi;H. Kaji;I. Kanazawa;T. Sugimoto
晚期糖基化终产物（AGEs）参与糖尿病骨质量的恶化。我们以前发现，AGE 2或AGE 3抑制小鼠基质ST 2细胞的成骨细胞分化和矿化，也诱导凋亡和细胞生长下降。虽然内质网（ER）中合成蛋白质的质量管理对于成骨细胞的成熟至关重要，但AGEs对成骨细胞系ER应激的影响尚不清楚。因此，我们研究了ER应激在AGE 2或AGE 3诱导的ST 2细胞成骨细胞生成抑制中的作用。ER应激诱导剂毒胡萝卜素（TG）通过增加Osterix、1型胶原（Col1）、碱性磷酸酶（ALP）和骨钙素（OCN）mRNA的水平诱导ST 2细胞向成骨细胞分化。AGE 2或AGE 3抑制ER应激传感器如IRE1α、ATF 6和OASIS的水平，而增加PERK及其下游分子ATF 4的水平。通过siRNA降低PERK水平并不影响AGEs诱导的Osterix、Col1和OCN mRNA水平的抑制。总之，AGEs通过抑制ER应力传感器和细胞中异常蛋白的积累来抑制基质细胞的成骨分化。这一过程可能会加速AGEs诱导的糖尿病患者骨形成抑制。
Advanced glycation end products (AGEs) are involved in bone quality deterioration in diabetes mellitus. We previously showed that AGE2 or AGE3 inhibited osteoblastic differentiation and mineralization of mouse stromal ST2 cells, and also induced apoptosis and decreased cell growth. Although quality management for synthesized proteins in endoplasmic reticulum (ER) is crucial for the maturation of osteoblasts, the effects of AGEs on ER stress in osteoblast lineage are unknown. We thus examined roles of ER stress in AGE2- or AGE3-induced suppression of osteoblastogenesis of ST2 cells. An ER stress inducer, thapsigargin (TG), induced osteoblastic differentiation of ST2 cells by increasing the levels of Osterix, type 1 collagen (Col1), alkaline phosphatase (ALP) and osteocalcin (OCN) mRNA. AGE2 or AGE3 suppressed the levels of ER stress sensors such as IRE1α, ATF6 and OASIS, while they increased the levels of PERK and its downstream molecules, ATF4. A reduction in PERK level by siRNA did not affect the AGEs-induced suppression of the levels of Osterix, Col1 and OCN mRNA. In conclusion, AGEs inhibited the osteoblastic differentiation of stromal cells by suppressing ER stress sensors and accumulating abnormal proteins in the cells. This process might accelerate AGEs-induced suppression of bone formation found in diabetes mellitus.