The Key Laboratory for Oral Biomedical Engineering of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China.
J Cell Physiol. 2010 Oct;225(1):106-14. doi: 10.1002/jcp.22201.
Although Porphyromonas gingivalis lipopolysaccharide (P-LPS) is known to inhibit osteoblast differentiation, the exact molecular mechanisms underlying this phenomenon remain unclear. Here, we investigated the role of Notch signaling in the osteoblastic differentiation of both MC3T3E-1 cells and primary mouse bone marrow stromal cells (BMSCs). P-LPS stimulation activated the Notch1 signaling cascade and increased expression of the Notch target genes HES1 and HEY1. P-LPS can also act as an inhibitor because it is capable of suppressing Wnt/beta-catenin signaling in preosteoblasts by decreasing both glycogen synthase kinase-3beta (GSK-3beta) phosphorylation and the expression of nuclear beta-catenin. These effects were rescued, however, by inhibiting Notch1 signaling. Furthermore, P-LPS treatment inhibited osteoblast differentiation in preosteoblasts as demonstrated by reductions in alkaline phosphatase activity, osteoblast gene expression, and mineralization, all of which were rescued by suppression of Notch1 signaling. Moreover, inhibition of GSK-3beta, HES1, or HEY1 partially reversed the P-LPS-induced inhibition of osteoblast differentiation. Together, these findings suggest that P-LPS inhibits osteoblast differentiation by promoting the expression of Notch target genes and suppressing canonical Wnt/beta-catenin signaling.
虽然牙龈卟啉单胞菌脂多糖（P-LPS）已被证实可抑制成骨细胞分化，但这一现象的确切分子机制仍不清楚。在此，我们研究了 Notch 信号通路在 MC3T3E-1 细胞和原代小鼠骨髓基质细胞（BMSCs）成骨分化中的作用。P-LPS 刺激激活了 Notch1 信号级联反应，增加了 Notch 靶基因 HES1 和 HEY1 的表达。P-LPS 还可以作为抑制剂，因为它能够通过降低糖原合酶激酶-3β（GSK-3β）磷酸化和核β-catenin 的表达，抑制前成骨细胞中的 Wnt/β-catenin 信号通路。然而，抑制 Notch1 信号通路可以挽救这些效应。此外，P-LPS 处理抑制了前成骨细胞中的成骨细胞分化，表现为碱性磷酸酶活性、成骨细胞基因表达和矿化减少，所有这些都可以通过抑制 Notch1 信号通路得到挽救。此外，抑制 GSK-3β、HES1 或 HEY1 部分逆转了 P-LPS 诱导的成骨细胞分化抑制。总之，这些发现表明，P-LPS 通过促进 Notch 靶基因的表达和抑制经典 Wnt/β-catenin 信号通路来抑制成骨细胞分化。
