Elucidation for inflammatory cytokines-induced apoptosis in osteoblastic cells

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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