RANK-Associated Inhibitor (RAIN) in Osteoclast Formation

破骨细胞形成中的 RANK 相关抑制剂 (RAIN)

基本信息

  • 批准号:
    7215194
  • 负责人:
  • 金额:
    $ 20.67万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2003
  • 资助国家:
    美国
  • 起止时间:
    2003-07-15 至 2008-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Receptor activator of NF-kappaB (RANK) and its ligand (RANKL, also known as TRANCE/ODF/OPGL) are essential mediators of osteoclastogenesis and have been implicated in various diseases, which include rheumatoid arthritis, osteoporosis, giant cell tumor of bone, Paget's disease, metastatic breast cancer, multiple myeloma, and familial expansile osteolysis. Osteoprotegerin (OPG, also known as OCIF/TR1) is a soluble, decoy receptor that inhibits RANKL from binding to its cell surface receptor RANK. Activation of signaling pathways by RANK is mediated through its interaction with tumor necrosis factor receptor-associated factors (TRAFs). Mice deleted of RANKL, RANK, or TRAF6 lack osteoclasts and develop severe osteopetrosis while mice lacking OPG develop osteoporosis. Thus, RANKL and OPG are the governing factors that regulate normal bone homeostasis. The cytoplasmic domain of RANK interacts with TRAF1, 2, 3, 5, and 6, and our laboratory described the distinct regions of RANK that interact with TRAF2, 5, and 6. In an effort to identify other factors that interact with the cytoplasmic domain of RANK, we used a yeast two-hybrid approach and identified a novel protein, which we termed RAIN, for RANK-Associated Inhibitor, for its ability to inhibit RANKL-mediated osteoclast formation Both mouse and human cDNAs were cloned and contain an open reading frame of 241 and 242 residues, respectively. RAIN is a novel protein with no identifiable domains or motifs. RAIN coprecipitates with endogenous RANK in RAW264.7 (RAW) cells. Furthermore, RAIN interacts with TRAF2, TRAF5, and TRAF6 in RAW cells. To understand the function of RAIN, RAW cells stably expressing RAIN did not interfere with early RANKL signaling such as NF-kappaB, JNK, ERK, or p38 MAPK activation. However, RAIN expressing cells did not form multinucleated osteoclasts when stimulated with RANKL, although the cells were TRAP+ and the cell cycle inhibitor p27 was upregulated. Thus, it appears RAIN acts as a negative regulator of the fusion event during osteoclast differentiation. In support of this model, we established RAW cells stably expressing anti-sense RAIN. Surprisingly, we observed increased osteoclast number, which was observed as early as day 2. Additionally, RANKL treatment of RAW cells caused induction of RAIN mRNA and protein, which begins on day 2 and continues through day 5. Biochemical evidence suggests that RAIN may function by sequestering or preventing F-actin polymerizatio. Thus, we have identified a novel protein that interacts with RANK and TRAFs, and presumably controls the formation multi-nucleated osteoclasts. We propose to extend these studies to further our understanding of RAIN's function in osteoclastogenesis by pursing the following specific aims: (1) define the molecular interactions of RAIN and TRAFs; (2) determine the biochemical proteins of RAIN with respect to actin polymerization; and (3) determine the physiological role of RAIN by targeted gene disruption and transgenic mice expressing RAIN. The identification of RAIN and it function in controlling osteoclast formation will provide new insights into the mechanism of osteoclast formation and may provide a novel target for the development of pharmaceutical agents aimed at preventing unwanted bone destruction associated with metabolic bone disorders and cancers associated with osteolytic lesions.
描述(由申请人提供):NF-kappaB受体激活剂(RANK)及其配体(RANKL,也称为TRANCE/ODF/OPGL)是破骨细胞发生的重要介质,并与多种疾病有关,包括类风湿关节炎、骨质疏松症、骨巨细胞瘤、Paget病、转移性乳腺癌、多发性骨髓瘤和家族性扩张性骨溶解。骨保护素(OPG,也称为OCIF/TR1)是一种可溶性诱骗受体,可抑制RANKL与其细胞表面受体RANK结合。RANK通过与肿瘤坏死因子受体相关因子(TRAFs)的相互作用介导信号通路的激活。缺失RANKL、RANK或TRAF6的小鼠缺乏破骨细胞并发展为严重的骨质疏松症,而缺失OPG的小鼠发展为骨质疏松症。因此,RANKL和OPG是调节正常骨稳态的调控因子。

项目成果

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BRYANT G DARNAY其他文献

BRYANT G DARNAY的其他文献

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{{ truncateString('BRYANT G DARNAY', 18)}}的其他基金

TRAF6 E3 LIGASE FUNCTION IN OSTEOCLASTOGENESIS
TRAF6 E3 连接酶在破骨细胞生成中的功能
  • 批准号:
    7316361
  • 财政年份:
    2007
  • 资助金额:
    $ 20.67万
  • 项目类别:
TRAF6 E3 LIGASE FUNCTION IN OSTEOCLASTOGENESIS
TRAF6 E3 连接酶在破骨细胞生成中的功能
  • 批准号:
    7878093
  • 财政年份:
    2007
  • 资助金额:
    $ 20.67万
  • 项目类别:
TRAF6 E3 LIGASE FUNCTION IN OSTEOCLASTOGENESIS
TRAF6 E3 连接酶在破骨细胞生成中的功能
  • 批准号:
    7462392
  • 财政年份:
    2007
  • 资助金额:
    $ 20.67万
  • 项目类别:
TRAF6 E3 LIGASE FUNCTION IN OSTEOCLASTOGENESIS
TRAF6 E3 连接酶在破骨细胞生成中的功能
  • 批准号:
    7643289
  • 财政年份:
    2007
  • 资助金额:
    $ 20.67万
  • 项目类别:
RANK-Associated Inhibitor (RAIN) in Osteoclast Formation
破骨细胞形成中的 RANK 相关抑制剂 (RAIN)
  • 批准号:
    6778140
  • 财政年份:
    2003
  • 资助金额:
    $ 20.67万
  • 项目类别:
RANK-Associated Inhibitor (RAIN) in Osteoclast Formation
破骨细胞形成中的 RANK 相关抑制剂 (RAIN)
  • 批准号:
    6881452
  • 财政年份:
    2003
  • 资助金额:
    $ 20.67万
  • 项目类别:
RANK-Associated Inhibitor (RAIN) in Osteoclast Formation
破骨细胞形成中的 RANK 相关抑制剂 (RAIN)
  • 批准号:
    6681774
  • 财政年份:
    2003
  • 资助金额:
    $ 20.67万
  • 项目类别:
RANK-Associated Inhibitor (RAIN) in Osteoclast Formation
破骨细胞形成中的 RANK 相关抑制剂 (RAIN)
  • 批准号:
    7050620
  • 财政年份:
    2003
  • 资助金额:
    $ 20.67万
  • 项目类别:
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