Department of Internal Medicine 1, Shimane University Faculty of Medicine, Izumo, Japan.
Biochem Biophys Res Commun. 2013 Aug 30;438(3):463-7. doi: 10.1016/j.bbrc.2013.07.126. Epub 2013 Aug 7.
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.
晚期糖基化终产物（AGEs）参与糖尿病患者的骨质量恶化。我们之前曾表明，AGE2 或 AGE3 抑制了小鼠基质 ST2 细胞的成骨细胞分化和矿化，并诱导了细胞凋亡和细胞生长减少。尽管内质网（ER）中合成蛋白的质量管理对于成骨细胞的成熟至关重要，但 AGEs 对成骨细胞谱系中的 ER 应激的影响尚不清楚。因此，我们研究了 ER 应激在 AGE2 或 AGE3 抑制 ST2 细胞成骨细胞发生中的作用。ER 应激诱导剂他普西醇（TG）通过增加 Osterix、I 型胶原（Col1）、碱性磷酸酶（ALP）和骨钙素（OCN）mRNA 的水平诱导 ST2 细胞的成骨细胞分化。AGE2 或 AGE3 抑制 ER 应激传感器（如 IRE1α、ATF6 和 OASIS）的水平，同时增加 PERK 及其下游分子 ATF4 的水平。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 应激传感器和在细胞中积累异常蛋白来抑制基质细胞的成骨细胞分化。这个过程可能会加速糖尿病中发现的 AGEs 诱导的骨形成抑制。
