Induction of DC-STAMP by alternative activation and downstream signaling mechanisms
Induction of DC-STAMP by alternative activation and downstream signaling mechanisms
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DOI：
10.1359/jbmr.070401
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发表时间：
2007-07-01
影响因子：
6.2
通讯作者：
Miyamoto, Takeshi
中科院分区：
文献类型：
--
作者：
Yagi, Mitsuru;Ninomiya, Ken;Miyamoto, Takeshi
DC-STAMP对于破骨细胞和异物巨细胞的融合是必不可少的;然而，目前尚不清楚这两种细胞类型中的DC-STAMP表达是否受到差异调节。在这里，我们表明，直流邮票的表达和细胞-细胞融合的调节在一个细胞类型特异性marty.Introduction：转录因子c-Fos和NFATc 1合作，以调节破骨细胞的分化，而PU.1和NF-κ B激活巨噬细胞和破骨细胞或在这两种细胞类型。因此，我们问什么样的作用c-Fos，NFATc 1，PU.1，和NF-κ B发挥调节树突状细胞特异性跨膜蛋白（dc-邮票）的表达和融合的破骨细胞和巨噬细胞giant cells.Materials and Methods：转录激活c-Fos和NFATc 1进行了检查，由dc-邮票启动子分析。在来自c-Fos缺陷型小鼠的细胞或用NFAT抑制剂FK 506处理的野生型细胞中分析多核细胞形成。在体外使用DC-STAMP缺陷细胞在巨噬细胞巨细胞形成测定中检查DC-STAMP在细胞融合中的作用。招募c-Fos，NFATc 1，PU.1，和NF-κ B的dc-stamp启动子中的破骨细胞和巨噬细胞进行了分析，通过染色质免疫沉淀analysis.Results：两个激活蛋白-1（AP-1）和NFAT结合位点的dc-stamp启动子中所需的破骨细胞RANKL刺激后的dc-stamp表达。在破骨细胞和巨噬细胞中诱导了DC-STAMP表达，DC-STAMP缺陷小鼠的细胞不能形成多核破骨细胞或巨噬细胞。与此相反，c-Fos是必不可少的条件下，有利于在体外和体内诱导破骨细胞，但不是巨噬细胞巨细胞的dc-stamp的表达和细胞-细胞融合。因此，NFAT抑制剂抑制多核破骨细胞形成，但不抑制巨噬细胞巨细胞形成。此外，在dc-stamp启动子中检测到PU.1和NF-KB结合位点，并且在粒细胞-巨噬细胞集落刺激因子（GM-CSF）+白细胞介素（IL）-4刺激后，PU.1和NF-KB均被募集到dc-stamp启动子中。c-Fos和NFATc 1都是破骨细胞分化所必需的，是破骨细胞中dc-stamp表达和细胞-细胞融合所必需的，但这两种因子都是巨噬细胞形成巨细胞所必需的。因为PU.1和NF-κ B在用GM-CSF + IL-4刺激后被募集到dc-stamp启动子，所以dc-stamp转录以细胞类型特异性方式调节。
DC-STAMP is essential for fusion of osteoclasts and foreign body giant cells; however, it is not known whether dc-stamp expression in these two cell types is differentially regulated. Here, we show that dc-stamp expression and cell-cell fusion are regulated in a cell type-specific manner.Introduction: The transcription factors c-Fos and NFATc1 cooperate to regulate osteoclast differentiation, whereas PU.1 and NF-KB are activated in macrophages and osteoclasts or in both cell types. Thus, we asked what role c-Fos, NFATc1, PU.1, and NF-KB played in regulating dendritic cell-specific transmembrane protein (dc-stamp) expression and fusion of osteoclasts and macrophage giant cells.Materials and Methods: Transcriptional activation by c-Fos and NFATc1 was examined by dc-stamp promoter analysis. Multinuclear cell formation was analyzed in cells from c-Fos-deficient mice or in wildtype cells treated with the NFAT inhibitor FK506. The role of DC-STAMP in cell fusion was examined in vitro in a macrophage giant cell formation assay using DC-STAMP-deficient cells. Recruitment of c-Fos, NFATc1, PU.1, and NF-KB to the dc-stamp promoter in osteoclasts and macrophage giant cells was analyzed by chromatin-immunoprecipitation analysis.Results: Both activator protein-1 (AP-1) and NFAT binding sites in the dc-stamp promoter were needed for dc-stamp expression after RANKL stimulation of osteoclasts. dc-stamp expression was induced in osteoclasts and macrophage giant cells, and cells from DC-STAMP-deficient mice failed to form either multinuclear osteoclasts or macrophage giant cells. In contrast, c-Fos is indispensable for dc-stamp expression and cell-cell fusion under conditions favoring in vitro and in vivo induction of osteoclasts but not macrophage giant cells. Consistently, an NFAT inhibitor suppressed multinuclear osteoclast formation but not macrophage giant cell formation. In addition, PU.1 and NF-KB binding sites were detected in the dc-stamp promoter, and both PU.1 and NF-KB were recruited to the dc-stamp promoter after granulocyte-macrophage colony stimulating factor (GM-CSF) + interleukin (IL)-4 stimulation.Conclusions: dc-stamp expression is regulated differently in osteoclasts and macrophage giant cells. c-Fos and NFATc1, both of which are essential for osteoclast differentiation, are needed for dc-stamp expression and cell-cell fusion in osteoclasts, but both factors are dispensable for giant cell formation by macrophages. Because PU.1 and NF-KB are recruited to the dc-stamp promoter after stimulation with GM-CSF + IL-4, dc-stamp transcription is regulated in a cell type-specific manner.