Elucidation for inflammatory cytokines-induced apoptosis in osteoblastic cells

1)2000年至2001年：在小鼠成骨细胞系MC 3 T3-E1中研究了促炎细胞因子引起的凋亡信号传导与丝裂原活化蛋白（MAP）激酶活化的关系。细胞因子引起的诱导型一氧化氮合酶（iNOS）mRNA和一氧化氮（NO）在细胞中的有效增强。p38 MAP激酶的特异性抑制剂，即，SB 203580以剂量依赖性方式抑制细胞因子处理的细胞中iNOS mRNA、其酶产物、NO和DNA片段化（作为凋亡指数）的诱导（*p<0.01），从而表明p38 MAP激酶级联在调节成骨细胞中iNOS依赖性死亡系统的诱导中具有重要作用。综上所述，在小鼠成骨细胞（制备中）中，苦参碱诱导的凋亡性细胞死亡是由p38 MAP激酶依赖的iNOS系统介导的。2）2001年至2002年：细胞因子的组合激活了Fas-Fas配体（FasL）依赖的死亡系统。细胞因子可引起Fas mRNA、Fas蛋白和Fas受体表达的增强， ...更多信息 ein，并导致凋亡性细胞死亡。外源性FasL导致细胞活力下降和细胞凋亡的细胞死亡的细胞因子预处理的细胞中，有力的增加，表明Fas-FasL系统有可能导致成骨细胞凋亡。总之，在小鼠成骨细胞中，马槟榔碱诱导的凋亡性细胞死亡由自分泌或旁分泌Fas-FasL死亡系统介导（Ozeki等人，口腔生物学文献，2002）.3）2002 - 2003：骨保护素（OPG）是最近发现的一种细胞因子，属于肿瘤坏死因子受体超家族，通过抑制骨细胞骨吸收来调节骨量。骨形态发生蛋白（BMP）-4显著增加小鼠骨髓基质细胞系ST 2中可溶性OPG的水平。体外免疫复合物激酶试验显示BMP-4可激活p38丝裂原活化蛋白激酶（MAP），SB 203580预处理可抑制BMP-4诱导的ST 2细胞OPG。这些结果清楚地表明，p38 MAP激酶途径的激活对于骨髓基质细胞中BMP-4诱导的OPG诱导是必需的（Tazoe等人，口腔生物学文献，印刷中）。少

1) 2000〜2001 : The apoptotic signaling by proinflammatory cytokines was studied in a mouse osteoblastic cell line, MC3T3-E1 in relation to mitogen-activated protein (MAP) kinase activation. Cytokines caused potent enhancement of inducible nitric oxide synthase (iNOS) mRNA and nitric oxide (NO) in the cells. A specific inhibitor of p38MAP kinase, i.e., SB203580, inhibited the induction of iNOS mRNA, its enzyme product, NO, and DNA fragmentation (as an apoptosis index) in cytokines-treated cells in a dose-dependent manner (*p<0.01), thereby suggesting a significant role for the p38MAP kinase cascade in regulating the induction of iNOS-dependent death system in osteoblastic cells. Taken together, cytokine-induced apoptotic cell death was mediated by p38MAP kinase-dependent iNOS system in mouse osteoblastic cells (in preparation).2) 2001〜2002 : The combination of cytokine activated the Fas-Fas Ligand (FasL)-dependent death system. Cytokines caused a potent enhancement of Fas mRNA, Fas prot … More ein, and led to apoptotic cell death. Exogenous FasL caused a decrease in cell viability and a potent increase in apoptotic cell death in the cells pretreated with cytokines, indicating that the Fas-FasL system has a potential to cause apoptosis in osteoblastic cells. Taken together, cytokine-induced apoptotic cell death was mediated by the autocrine or paracrine Fas-FasL death system in mouse osteoblastic cells (Ozeki et al., Archs Oral Biol., 2002).3) 2002〜2003 : Osteoprotegerin (OPG) is a recently identified cytokine that belongs to the tumor necrosis factor receptor superfamily and regulates bone mass by inhibiting osteoclastic bone resorption. Bone morphogenetic protein (BMP)-4 markedly increased the level of soluble OPG in the mouse bone marrow-derived stromal cell line, ST2. BMP-4 causes the activation of p38 mitogen-activated protein (MAP) kinase using in vitro immunocomplex kinase assay, Pretreatment of ST2 cells with SB203580 inhibited the BMP-4-induced OPG. These results clearly suggest that the activation of the p38MAP kinase pathway is necessary for BMP-4-induced OPG induction in bone marrow stromal cells (Tazoe et al., Archs Oral Biol., in press). Less