Advanced Glycation End Product 3 (AGE3) Suppresses the Mineralization of Mouse Stromal ST2 Cells and Human Mesenchymal Stem Cells by Increasing TGF-β Expression and Secretion
Advanced Glycation End Product 3 (AGE3) Suppresses the Mineralization of Mouse Stromal ST2 Cells and Human Mesenchymal Stem Cells by Increasing TGF-β Expression and Secretion
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DOI：
10.1210/en.2013-1818
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发表时间：
2014-07-01
期刊：
影响因子：
4.8
通讯作者：
Sugimoto, Toshitsugu
中科院分区：
文献类型：
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作者：
Notsu, Masakazu;Yamaguchi, Toru;Sugimoto, Toshitsugu
在糖尿病患者中，晚期糖基化终末产物(AGEs)会由于骨骼质量的恶化而导致骨脆性。我们之前发现AGEs抑制了小鼠基质ST2细胞的矿化。转化生长因子-β在骨骼中含量丰富，其信号的增强会导致骨骼质量的恶化。然而，在成骨细胞分化过程中，转化生长因子-β信号是否参与了年龄诱导的矿化抑制尚不清楚。因此，我们研究了转化生长因子-β在年龄诱导的抑制ST2细胞和人间充质干细胞矿化中的作用。AGE3显著(P<；.001)抑制这两种细胞的矿化，而转染AGEs受体(RAGE)的小干扰RNA显著(P<；.05)恢复ST2细胞的这一过程。AGE_3可增加细胞内转化生长因子-β的mRNA和蛋白的表达，RAGE小干扰RNA可部分拮抗该作用。用转化生长因子-βI型受体激酶抑制剂SD208处理ST2细胞，可恢复AGE3诱导的骨钙素(P<；.001)和骨钙素(P<；.05)的减少，并拮抗AGE_3诱导的ST2细胞Runx2基因表达的增加(P<；.001)。此外，SD208完全和剂量依赖地挽救了AGE3对两种细胞矿化的抑制作用。相反，SD208增强了AGE3诱导的细胞增殖抑制以及AGE3诱导的ST2细胞的凋亡。这些结果表明，在细胞融合后，AGE3通过与RAGE结合，增加转化生长因子-β的表达和分泌，部分抑制成骨细胞的分化和矿化。他们还表明，转化生长因子-β不仅对原发性骨质疏松症有不利影响，而且对糖尿病相关的骨病也有不利影响。
In diabetic patients, advanced glycation end products (AGEs) cause bone fragility because of deterioration of bone quality. We previously showed that AGEs suppressed the mineralization of mouse stromal ST2 cells. TGF-beta is abundant in bone, and enhancement of its signal causes bone quality deterioration. However, whether TGF-beta signaling is involved in the AGE-induced suppression of mineralization during the osteoblast lineage remains unknown. We therefore examined the roles of TGF-beta in the AGE-induced suppression of mineralization of ST2 cells and human mesenchymal stem cells. AGE3 significantly (P < .001) inhibited mineralization in both cell types, whereas transfection with small interfering RNA for the receptor for AGEs (RAGEs) significantly (P < .05) recovered this process in ST2 cells. AGE3 increased (P < .001) the expression of TGF-beta mRNA and protein, which was partially antagonized by transfection with RAGE small interfering RNA. Treatment with a TGF-beta type I receptor kinase inhibitor, SD208, recovered AGE3-induced decreases in osterix (P < .001) and osteocalcin (P < .05) and antagonized the AGE3-induced increase in Runx2 mRNA expression in ST2 cells (P < .001). Moreover, SD208 completely and dose dependently rescued AGE3-induced suppression of mineralization in both cell types. In contrast, SD208 intensified AGE3-induced suppression of cell proliferation as well as AGE3-induced apoptosis in proliferating ST2 cells. These findings indicate that, after cells become confluent, AGE3 partially inhibits the differentiation and mineralization of osteoblastic cells by binding to RAGE and increasing TGF-beta expression and secretion. They also suggest that TGF-beta adversely affects bone quality not only in primary osteoporosis but also in diabetes-related bone disorder.