IL-1 regulates cytoskeletal organization in osteoclasts via TNF receptor-associated factor 6/c-Src complex
IL-1 regulates cytoskeletal organization in osteoclasts via TNF receptor-associated factor 6/c-Src complex
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DOI：
10.4049/jimmunol.168.10.5103
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发表时间：
2002-05-15
影响因子：
4.4
通讯作者：
Duong, LT
中科院分区：
文献类型：
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作者：
Nakamura, I;Kadono, Y;Duong, LT
C-Src或TNFR相关因子6(TRAF6)在小鼠体内的靶向性破坏会导致破骨细胞功能障碍和成骨表型，提示这两个分子在破骨细胞性骨吸收中发挥重要作用。我们先前证明了IL-1诱导肌动蛋白环的形成和破骨细胞的激活。在这项研究中，我们研究了IL-1/TRAF6依赖和c-Src介导的途径在小鼠共培养体系中形成的破骨细胞样细胞(前融合细胞；多核细胞)激活中的关系。在正常卵巢癌中，IL-1诱导肌动蛋白环的形成和c-Src的底物p130(Cas)的酪氨酸磷酸化。然而，在Src缺乏的POCs中，p130(Cas)在IL-1处理后不被酪氨酸磷酸化。在经IL-1处理的正常POCs中，抗TRAF6抗体共沉淀p130(Cas)、蛋白酪氨酸激酶2和c-Src。在缺乏Src的POCs中，没有检测到这种分子复合体，这表明c-Src是形成TRAF6、p130(Cas)和蛋白酪氨酸激酶2复合体所必需的。此外，免疫细胞化学分析显示，在破骨细胞样多核细胞中，IL-1诱导TRAF6重新分布到细胞外围形成的肌动蛋白环结构，其中TRAF6也与c-Src共存。综上所述，这些数据表明，IL-1信号通过TRAF6-Src分子复合体进入酪氨酸激酶途径，TRAF6-Src分子复合体调节破骨细胞激活所必需的细胞骨架重组。
Targeted disruption of either c-Src or TNFR-associated factor 6 (TRAF6) in mice causes osteoclast dysfunction and an osteopetrotic phenotype, suggesting that both molecules play important roles in osteoclastic bone resorption. We previously demonstrated that IL-1 induces actin ring formation and osteoclast activation. In this study, we examined the relationship between IL-1/TRAF6-dependent and c-Src-mediated pathways in the activation of osteoclast-like cells (prefusion cells (pOCs); multinucleated cells) formed in the murine coculture system. In normal pOCs, IL-1 induces actin ring formation and tyrosine phosphorylation of p130(Cas), a known substrate of c-Src. However, in Src-deficient pOCs, p130(Cas), was not tyrosine phosphorylated following IL-1 treatment. In normal pOCs treated with IL-1, anti-TRAF6 Abs coprecipitate p130(Cas), protein tyrosine kinase 2, and c-Src. In Src-deficient pOCs, this molecular complex was not detected, suggesting that c-Src is required for formation of the TRAF6, p130(Cas), and protein tyrosine kinase 2 complex. Moreover, an immunocytochemical analysis revealed that in osteoclast-like multinucleated cells, IL-1 induced redistribution of TRAF6 to actin ring structures formed at the cell periphery, where TRAF6 also colocalized with c-Src. Taken together, these data suggest that IL-1 signals feed into the tyrosine kinase pathways through a TRAF6-Src molecular complex, which regulates the cytoskeletal reorganization essential for osteoclast activation.