Monokine induced by interferon-γ is induced by receptor activator of nuclear factor κB ligand and is involved in osteoclast adhesion and migration
Monokine induced by interferon-γ is induced by receptor activator of nuclear factor κB ligand and is involved in osteoclast adhesion and migration
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DOI：
10.1182/blood-2004-07-2534
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发表时间：
2005-04-01
期刊：
影响因子：
20.3
通讯作者：
Lee, ZH
中科院分区：
文献类型：
--
作者：
Kwak, HB;Lee, SW;Lee, ZH
骨重建伴随着来自造血细胞的单核细胞/巨噬细胞谱系的破骨细胞的分化。破骨细胞的分化过程需要核因子κ B（NF-κ B）配体（RANKL）的受体激活剂，这会导致各种基因表达的复杂变化。在鉴定RANKL靶向基因的cDNA微阵列研究中，我们发现由干扰素-γ（IFN-γ）（IFN-γ）基因诱导的单核因子在破骨细胞前体细胞中上调。通过逆转录-聚合酶链反应和蛋白质印迹分析证实RANKL增加了TGFAP表达。RANKL诱导TNF α需要NF-κ B的活性，其结合位点存在于TNF α启动子中。RANKL的TNF-α诱导也依赖于p38丝裂原活化蛋白激酶（MAPK）和信号转导和转录激活因子1（STAT 1）。RANKL刺激STAT 1的Ser 727磷酸化，这需要p38活性。RANKL处理后分泌的MIG可以刺激破骨细胞前体和破骨细胞的迁移和粘附，这些破骨细胞通过巨噬细胞集落刺激因子（M-CSF）启动表达CXCR 3（MIG受体）。因此，我们提供了第一个证据，证明RANKL通过p38 MAPK通路刺激STAT 1的丝氨酸磷酸化，引起CXCR 3基因转录和分泌，这可能在招募CXCR 3阳性破骨细胞前体和破骨细胞到骨重建或炎症部位中发挥作用。
Bone remodeling is accompanied by the differentiation of osteoclasts from the monocyte/macrophage lineage of hematopoietic cells. The osteoclast differentiation process requires receptor activator of nuclear factor kappa B (NF-kappa B) ligand (RANKL), which causes complex changes in the expression of various genes. In a cDNA microarray study to identify genes targeted by RANKL, we found that monokine induced by the interferon-gamma (IFN-gamma) (MIG) gene was up-regulated in osteoclast precursor cells. The increase in MIG expression by RANKL was confirmed by reverse transcription-polymerase chain reaction and Western blot analysis. RANKL induction of MIG required the activity of NF-kappa B, whose binding site is present in the MIG promoter. MIG induction by RANKL was also dependent on p38 mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 1 (STAT1). RANKL stimulated the phosphorylation of Ser727 of STAT1, which required p38 activity. MIG secreted on RANKL treatment could stimulate the migration and adhesion of osteoclast precursors and osteoclasts that were primed to express CXCR3, the MIG receptor, by macrophage-colony-stimulating factor (M-CSF). Therefore, we provide the first evidence demonstrating that RANKL stimulates the serine phosphorylation of STAT1 through the p38 MAPK pathway, causing MIG gene transcription and secretion, which may have a role in recruiting CXCR3-positive osteoclast precursors and osteoclasts to bone remodeling or inflammatory sites.