The PI3K/AKT pathway promotes fracture healing through its crosstalk with Wnt/β-catenin.

Experimental Cell Research
Jun DongBingyi Tan

Abstract

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/β-catenin pathway plays an essential role in bone regeneration. However, whether there exists crosstalk between Wnt/β-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-3β at Ser9 and phosphorylation of β-catenin at Ser552 in fracture callus and murine osteoblastic MC3T3-E1 cells, both of which lead to β-catenin stabilization, nuclear translocation, as well as β-catenin-mediated TCF-dependent transcription, suggesting that β-catenin is activated downstream of PI3K/AKT. Furthermore, we show that ICG001, the inhibitor of β-catenin transcriptional activity, attenuates PI3K/AKT-induced osteoblast proliferation,...Continue Reading

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