Notch信号通路在BMP9诱导间充质干细胞成骨分化中的作用研究

Notch signaling is one of the most important pathways in regulating progenitor cell proliferation and differentiation. In our previous research, we found that overexpression of Notch ligand DLL1 enhanced BMP9’s ability to induce osteogenic differentiation of mesenchymal stem cells(MSCs); that inhibition of the key Notch pathway enzyme γ-secretase activity led to a decrease in BMP9-induced osteoblast differentiation, suggesting that BMP9-induced bone formation may require the participation of Notch signaling.The goal of this study is 1) to determine if Notch signaling plays an important role in BMP9-induced bone formation of MSCs by investigating the changes of BMP9-induced osteogenic differentiation in different interventions of Notch signaling; 2) to delineate the molecular mechanisms through which BMP9 promotes cell proliferation and induces osteogenic differentiation of MSCs by exploring the changes of cell cycle and expression of osteogenesis markers; and 3）to pinpoint BMP9’s molecular regulation on Notch pathway through analyzing the expression changes of key molecules of Notch pathway under BMP9 treatment.As the role of Notch signaling in BMP9-induced bone formation of MSCs have never been investigated, our proposed work is innovative and of significance. A successful completion of the proposed work should expand our understanding about the molecular basis of BMP9 signaling, which may ultimately lead to the clinical application of BMP9 to induce bone regeneration and prevent orthoporosis.

Notch信号通路是参与调控干细胞增殖和分化的重要通路之一。我们前期发现：Notch配体DLL1过表达能增加BMP9诱导间充质干细胞（MSCs）成骨分化的作用；Notch关键酶γ-分泌酶被抑制，BMP9诱导成骨分化作用降低，提示Notch可能在BMP9诱导MSCs成骨分化中发挥重要作用。本课题拟：研究Notch信号通路在不同干预情况下，BMP9诱导成骨作用的变化，验证Notch信号通路在BMP9诱导MSCs成骨分化中发挥重要作用；探究细胞周期和成骨标志物表达变化，评判BMP9促进MSCs增殖，诱导成骨分化的机制；分析Notch通路关键分子在BMP9作用下的表达变化，揭示BMP9对Notch通路分子的调控作用。Notch信号通路在BMP9诱导MSCs成骨分化中的作用未见报道，本研究具有创新性和指导意义，有助于深入了解BMP9诱导成骨分化的机制，推动临床应用BMP9促进骨再生防治骨科疾病。