The PI3K/AKT pathway promotes fracture healing through its crosstalk with Wnt/β-catenin
The PI3K/AKT pathway promotes fracture healing through its crosstalk with Wnt/β-catenin
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DOI：
10.1016/j.yexcr.2020.112137
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发表时间：
2020-09-01
影响因子：
3.7
通讯作者：
Tan, Bingyi
中科院分区：
文献类型：
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作者：
Dong, Jun;Xu, Xiqiang;Tan, Bingyi
PI 3 K/AKT是调节细胞凋亡、增殖和分化等细胞行为的关键通路之一。尽管先前的研究已经证明该通路是成骨细胞的关键调节因子，但PI 3 K/AKT在骨折愈合中的作用仍不清楚。众所周知，Wnt/β-连环蛋白通路在骨再生中起着重要作用。然而，Wnt/beta-catenin和PI 3 K/AKT在调控成骨细胞和骨修复中是否存在相互作用尚未见报道。为了解决这些问题，我们在小鼠中建立了稳定的骨折模型，并表明PI 3 K抑制剂LY 294002基本上抑制了骨愈合过程，表明PI 3 K/AKT促进骨折修复。更重要的是，我们报告说，PI 3 K/AKT增加磷酸化的GSK-3 β在Ser 9和磷酸化的β-连环蛋白在Ser 552骨折骨痂和小鼠成骨细胞MC 3 T3-E1细胞，这两个导致β-连环蛋白的稳定，核转位，以及β-连环蛋白介导的TCF依赖性转录，这表明β-连环蛋白被激活的PI 3 K/ AKT下游。此外，我们发现ICG 001，β-连环蛋白转录活性的抑制剂，减弱PI 3 K/AKT诱导的成骨细胞增殖，分化和矿化，表明PI 3 K/AKT/β-连环蛋白轴在调节成骨细胞中起作用。值得注意的是，PI 3 K/AKT通路也被Wnt 3a激活，并参与Wnt 3a诱导的成骨细胞增殖和分化。因此，我们的结果揭示了成骨细胞中存在Wnt/PI 3 K/AKT/β-连环蛋白信号联系，强调了PI 3 K/AKT和Wnt/β-连环蛋白途径之间复杂的串扰，这与骨折愈合密切相关。
PI3K/AKT is one of the key pathways that regulate cell behaviors including apoptosis, proliferation, and differentiation. Although previous studies have demonstrated that this pathway is a crucial regulator of osteoblasts, the role of PI3K/AKT in fracture healing remains unclear. It is well known that the Wnt/beta-catenin pathway plays an essential role in bone regeneration. However, whether there exists crosstalk between Wnt/beta-catenin and PI3K/AKT in regulating osteoblasts and bone repair has not been reported. To address these issues, we establish a stabilized fracture model in mice and show that PI3K inhibitor LY294002 substantially inhibits the bone healing process, suggesting that PI3K/AKT promotes fracture repair. More importantly, we report that PI3K/AKT increases phosphorylation of GSK-3 beta at Ser9 and phosphorylation of beta-catenin at Ser552 in fracture callus and murine osteoblastic MC3T3-E1 cells, both of which lead to beta-catenin stabilization, nuclear translocation, as well as beta-catenin-mediated TCF-dependent transcription, suggesting that beta-catenin is activated downstream of PI3K/ AKT. Furthermore, we show that ICG001, the inhibitor of beta-catenin transcriptional activity, attenuates PI3K/AKT-induced osteoblast proliferation, differentiation, and mineralization, indicating that the PI3K/AKT/beta-catenin axis is functional in regulating osteoblasts. Notably, the PI3K/AKT pathway is also activated by Wnt3a and is involved in Wnt3a-induced osteoblast proliferation and differentiation. Hence, our results reveal the existence of a Wnt/PI3K/AKT/beta-catenin signaling nexus in osteoblasts, highlighting complex crosstalk between PI3K/AKT and Wnt/beta-catenin pathways that are critically implicated in fracture healing.