Department of Pediatrics, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8670, Japan.
Mol Cell Endocrinol. 2011 Jun 6;339(1-2):114-9. doi: 10.1016/j.mce.2011.04.003. Epub 2011 Apr 8.
AMP-activated protein kinase (AMPK) is a key sensor of cellular energetic conditions. Recent studies suggest that AMPK affects osteoblast differentiation, although its role and mechanism are not fully understood. One of the most important signals in osteoblast differentiation is the Wnt/β-catenin pathway which induces T-cell transcription factor 1 (TCF)-dependent transcription. Using human osteoblast-like Saos-2 cells, we determined whether AMPK modulates Wnt/β-catenin signaling in osteoblasts. Chemical activators of AMPK (AICAR [5-aminoimidazole-4-carboxamide riboside], metformin) suppressed Wnt3a-induced TCF-dependent transcriptional activity. Transactivation by Wnt was potentiated by inhibiting β-catenin degradation with lithium chloride (LiCl). LiCl-induced Wnt transactivation was suppressed by addition of metformin. Metformin increased the phosphorylation of β-catenin and decreased β-catenin protein levels leading to suppression of Wnt/β-catenin signaling. Our present study showed that AMPK attenuates Wnt/β-catenin signaling by reducing β-catenin protein levels in osteoblast-like cells.
AMP 激活的蛋白激酶 (AMPK) 是细胞能量状态的关键传感器。最近的研究表明，AMPK 影响成骨细胞分化，但其作用和机制尚不完全清楚。成骨细胞分化中最重要的信号之一是 Wnt/β-连环蛋白途径，它诱导 T 细胞转录因子 1 (TCF) 依赖性转录。使用人成骨样 Saos-2 细胞，我们确定 AMPK 是否调节成骨细胞中的 Wnt/β-连环蛋白信号。AMPK 的化学激活剂 (AICAR[5-氨基咪唑-4-甲酰胺核苷]、二甲双胍) 抑制 Wnt3a 诱导的 TCF 依赖性转录活性。用氯化锂 (LiCl) 抑制 β-连环蛋白降解增强 Wnt 的转导活性。二甲双胍抑制 LiCl 诱导的 Wnt 转导活性。二甲双胍增加 β-连环蛋白的磷酸化并降低 β-连环蛋白蛋白水平，从而抑制 Wnt/β-连环蛋白信号。本研究表明，AMPK 通过降低成骨样细胞中的 β-连环蛋白蛋白水平来减弱 Wnt/β-连环蛋白信号。
