Sphingosine-1-phosphate promotes the nuclear translocation of β-catenin and thereby induces osteoprotegerin gene expression in osteoblast-like cell lines

• Sphingosine-1-phosphate (S1P) activates PI3K/Akt signaling pathway.
• S1P promotes the nuclear translocation of β-catenin in osteoblasts.
• S1P induces osteoprotegerin gene expression.
• S1P promotes osteoblast differentiation and osteoblast-mediated mineralization.
• S1P is a potential lipid mediator of bone regeneration.

Sphingosine-1-phosphate (S1P) is a well-known signaling sphingolipid and bioactive lipid mediator. Recently, it was reported that S1P inhibits osteoclast differentiation and bone resorption. On the other hand, S1P effects on osteoblasts and bone formation are little known. In this study, we investigated the effects of S1P on osteoblasts, using two osteoblast-like cell lines, SaOS-2 and MC3T3-E1. S1P activated phosphatidylinositol 3-kinase (PI3K)/Akt signaling, leading to the inhibition of glycogen synthase kinase-3β and the nuclear translocation of β-catenin, followed by the increase of the transcriptional activity by β-catenin/T-cell factor complex formation in both SaOS-2 cells and MC3T3-E1 cells. The inhibitors of PI3K and Akt suppressed S1P-induced nuclear localization of β-catenin. We further investigated the effects of PI3K/Akt signaling on the Wnt/β-catenin signaling pathway, since β-catenin takes a central role in this signaling pathway. Both inhibitors for PI3K and Akt suppressed the nuclear localization of β-catenin and T-cell factor transcriptional activity induced by Wnt-3a. S1P increased the amount of osteoprotegerin at both mRNA and protein levels, and increased the activity of alkaline phosphatase, leading to the mineralization. These findings suggest that S1P activates the PI3K/Akt signaling pathway leading to the promotion of nuclear translocation of β-catenin in osteoblast-like cells, resulting in the upregulation of osteoptotegerin and osteoblast differentiation markers including alkaline phosphatase, probably relating to the inhibition of osteoclast formation and the mineralization, respectively.