模拟微重力对人骨髓间充质干细胞向成骨细胞分化中细胞信号通路影响的分析

通过模拟来研究微重力对hMSC向成骨细胞分化的影响,并利用相关信号通路的激活剂或抑制剂来调节这一分化过程.研究结果表明,在成骨细胞分化诱导条件下,微重力降低了hMSC向成骨细胞定向分化的能力,并且成骨细胞标记性基因的表达明显降低, Runt相关转录因子2(Ruax2)的表达受到抑制.相反,过氧化物酶体增殖激活受体γ(PPARγ2)的表达则增加.同时,微重力也降低了ERK的磷酸化水平,而增加了p38MAPK的磷酸化水平.使用p38MAPK的抑制剂SB203580能够抑制p38MAPK的磷酸化,但不能降低PPARγ2的表达水平.骨形态发生蛋白(BMP)能增加Runx2的表达水平.成纤维细胞生长因子2(FGF2)增加了ERK的磷酸化水平,但也不能显著增加成骨细胞标记性基因的表达水平.采用BMP,FGF2和SB203580三种因子组合来调控微重力下的成骨细胞分化能力,结果表明三者的协同作用能显著逆转微重力对成骨细胞定向分化的生物学效应.研究结果还说明,模拟微重力应该是通过不同的细胞信号通路来抑制成骨细胞分化和提升脂肪细胞分化的.

Analysis of Effects of Simulated Microgravity on Signaling Pathways Involved in Osteogenic Differentiation of Human Mesenchymal Stem Cells

Microgravity (MG) results in reduction of bone formation. Bone formation is bound up with osteogenic differentiation from human mesenchymal stem cells (hMSC) in bone marrow. We simulated MG to determine its effects on osteogenesis of hMSC and used activators or inhibitors of signaling factors to modulate osteogenic differentiation. Under osteogenic induction, MG reduceds osteogenic differentiation of hMSC and decreaseds the expression of osteoblast gene markers. The expression of Runx2 was likewise inhibited. However, the expression of PPAR$\g$2 increased. MG also decreased phosphorylation of ERK, but increased phosphorylation of p38MAPK. SB203580, a p38MAPK inhibitor, was able to inhibit the phosphorylation of p38MAPK, but not able to reduce the expression of PPARγ2. Bone morphogenetic protein (BMP) increased the expression of Runx2. Fibroblast growth factor 2 (FGF2) increased the phosphorylation of ERK, but did not increase significantly the expression of osteoblast gene markers. The combination of BMP, FGF2 and SB203580 significantly reversed the effect of MG on osteogenic differentiation of hMSC. Our results suggests that simulated MG inhibits the osteogenic differentiation and increases the adipogenic differentiation of hMSC through different signaling pathways. Therefore the effect of MG on the differentiation of hMSC could be reversed by the mediation of signaling pathways.