Elucidation of molecular mechanisms of osteoclastogenesis for developing drugs that inhibit bone resorption

阐明破骨细胞生成的分子机制，用于开发抑制骨吸收的药物

• 批准号: 18390409
• 负责人: INOUE Jun-ichiro
• 金额: $ 11.28万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390409/
• 关键词: signal transduction; development & differentiation; bone metabolism; drug discovery; bone metastasis; rheumatoid arthritis; osteoporosis

TRAF6 is essential for osteoclastogenesis and plays a crucial role in both RANK- and CD40-mediated activation of IKK and MAPKs in osteoclast progenitor cells. Despite the requirement for IKK and MAPKs activation in osteoclastogenesis, RANK, but not CD40, can promote osteoclastogenesis because only RANK can induce long-term activation of the co-stimulatory signals mediated by immunoglobulin-like receptors/ITAM-containing adaptors complexes, which are required for induction of NFATcl, a master gene in osteoclastogenesis. Our previous data suggested that RANK, but not CD40, harbors a unique domain that functions in concert with the TRAF6-binding site to activate the co-stimulatory signals in a sustainable way and promote osteoclastogenesis. We identify such a functional protein domain, HCR, that is highly conserved in RANKs from various vertebrates and is essential for long-term activation of co-stimulatory signals. Addition of the HCR to the cytoplasmic tail of CD40 renders CD40 capable of inducing sustained activation of co-stimulatory signals and subsequent activation of NFATcl. Furthermore, the HCR dramatically enhances internalization of HCR-harboring receptors upon stimulation. These results suggest that the HCR can continuously link the RANK-TRAF6 axis to sustained co-stimulatory signaling pathways through control of the membrane trafficking of receptors and that the HCR may be a novel therapeutic target for pathological bone resorption.

TRAF6对于破骨细胞生成至关重要，并且在破骨细胞祖细胞中IKK和MAPKS的等级和CD40介导的激活中起着至关重要的作用。 Despite the requirement for IKK and MAPKs activation in osteoclastogenesis, RANK, but not CD40, can promote osteoclastogenesis because only RANK can induce long-term activation of the co-stimulatory signals mediated by immunoglobulin-like receptors/ITAM-containing adaptors complexes, which are required for induction of NFATcl, a master gene in osteoclastogenesis.我们以前的数据表明，等级但不在CD40中，藏有一个独特的域，该领域与TRAF6结合位点起作用，以可持续的方式激活共刺激信号并促进骨质质构成。我们确定了这种功能性蛋白质结构域HCR，该结构域在各种脊椎动物的等级中高度保守，对于共同激活的共刺激信号至关重要。将HCR添加到CD40的细胞质尾巴中，使CD40能够诱导共刺激信号的持续激活并随后激活NFATCL。此外，HCR在刺激后大大增强了HCR量的受体的内在化。这些结果表明，通过控制受体的膜运输，HCR可以连续将Rank-Traf6轴与持续的共刺激信号通路联系起来，并且HCR可能是病理骨吸收的新型治疗靶标。

项目成果

疾患メカニズムの解明に向けたチロシンリン酸化ネットワークに関する包括的動態解析

酪氨酸磷酸化网络的综合动态分析阐明疾病机制

• 发表时间: 2007
• 作者: 松村隆之;井上純一郎;茂木秀彦;山崎孔輔;山口憲孝;尾山大明
• 通讯作者: 尾山大明

細胞シグナル伝達因子の制御による樹状細胞の人為的活性化

通过控制细胞信号因子人工激活树突状细胞

• 发表时间: 2007
• 作者: 秋山泰身;ら
• 通讯作者: ら

HTLV-1 Tax-induced NFκB activation is indepehdent of Lys-63-linked-typepolyubiquitination

HTLV-1 Tax 诱导的 NFκB 激活与 Lys-63 连接型多泛素化无关

• 发表时间: 2007
• 期刊: Biochem.Biophys.Res.Commun 357
• 作者: Gohda;J.
• 通讯作者: J.

I dentification of TRAF6 as a critical intracellular signal transducer for controlling auto immunity

I 鉴定 TRAF6 作为控制自身免疫的关键细胞内信号转导器

• 发表时间: 2007
• 作者: Qin;J.;Gohda J;Maezawa Y;Sharma RK;Ito H;Yamamoto T;Maezawa Y;Sharma RK;Ito H;Yamamoto T;Maezawa Y;Sharma RK;Ito H;Yamamoto T;井上純一郎;Jun-ichiro Inoue;仙波 憲太郎;秋山 泰身;松村 隆之;山崎孔輔;Kosuke Yamazaki;茂木 秀彦;山口 憲孝;田口祐;Yuu Taguchi;長谷 川恵一;尾山 大明;田口 祐;秦 裕子;宮坂 隆;仁科 隆史;山口 憲孝;尾山 大明;柴田 佑里;秦 裕子;秋山 泰身;井上純一郎;Jun-ichiro Inoue;Jun-ichiro Inoue
• 通讯作者: Jun-ichiro Inoue

TRAF6欠損によるTCR依存的なAP-1の活性化及び細胞増殖の充進

TRAF6 缺陷导致 AP-1 的 TCR 依赖性激活和细胞增殖增强

• 发表时间: 2007
• 作者: Qin;J.;Gohda J;Maezawa Y;Sharma RK;Ito H;Yamamoto T;Maezawa Y;Sharma RK;Ito H;Yamamoto T;Maezawa Y;Sharma RK;Ito H;Yamamoto T;井上純一郎;Jun-ichiro Inoue;仙波 憲太郎;秋山 泰身;松村 隆之;山崎孔輔;Kosuke Yamazaki;茂木 秀彦
• 通讯作者: 茂木 秀彦