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The relationship between cell proliferation and RANKL-induced osteoclastogenesis

细胞增殖与RANKL诱导的破骨细胞生成的关系

基本信息

批准号：
18390495
负责人：
TAKAHASHI Naoyuki
金额：
$ 11.15万
依托单位：
Matsumoto Dental University
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-18390495/
关键词：
Osteoclasts RANKL M-CSF Osteoblasts Cell cycle-arrested quiescent osteoclast precursor OPG Osteoclast niche Fos deficient mice 骨髄細胞マクロファージ RANK-Cre 骨髄マクロファージプロモデオキシウリジン

项目摘要

(1) In vitro analysis of the cell cycle in osteoclast progenitors : We have shown that cell cycle progression and withdrawal after the progression in osteoclast precursors are the two sequential events essential for RANKL-induced osteoclastogenesis.(2) The isolation and the analysis of QOPs: Cell cycle-arrested quiescent osteoclast precursors (QOPs) were identified as the committed osteoclast precursors in vitro. In vivo experiments showed that mononuclear cells expressing c-Fms and RANK but not Ki67 were detected along bone surfaces in the vicinity of osteoblasts in RANKL-deficient mice. They were identified as QOPs.(3) BMP transplantation experiments using RANKL(-/-) mice and OPG(-/-) mice : We examined the requirements for osteoclastogenesis using OPG(-/-) mice, RANKL(-/-) mice and a system involving BMP-induced ectopic bone formation. We have shown that osteoblasts also play important roles in osteoclastogenesis through offering the critical microenvironment for the action of RANKL.(4) Establishment of the Cre-lox P system for osteoclast specific deletion of target genes : We have succeeded to establish RANK Cre mice. We are now analyzing the Cre recombinase expression in osteoclastss.(5) Transgenic mice of cell cycle regulatory genes : We are advancing experiments on osteoclast niche, in stead of the production of the cycle regulatory gene transgenic mice.(6) Clinical application of anti-cancer drugs in bone diseases : We have shown that that taxanes have beneficial effects on the treatment of bone metastatic cancers. Administration of an anti-cancer drug, 5-fluorouracil, to mice induced myelosuppression, but QOPs survived and differentiated into osteoclasts in response to an active vitamin D_3 analog given to those mice. We have shown that QOPs pre-exist at the site of osteoclastogenesis and that osteoblasts play roles in the maintenance of QuOPs in the undifferentiated state. We found that c-Fos(-/-) mice have not osteoclast niche.

(1)破骨细胞前体细胞周期的体外分析：我们已经证明，破骨细胞前体细胞的细胞周期进展和进展后的退出是RANKL诱导的破骨细胞生成所必需的两个连续事件。(2)破骨细胞前体细胞的分离与鉴定：细胞周期停滞的静止期破骨细胞前体细胞（QOP）在体外被鉴定为定向破骨细胞前体细胞。体内实验表明，表达c-Fms和RANK但不表达Ki 67的单核细胞在RANKL缺陷小鼠成骨细胞附近的沿着骨表面检测。它们被识别为QOP。(3)使用RANKL（-/-）小鼠和OPG（-/-）小鼠的BMP移植实验：我们使用OPG（-/-）小鼠、RANKL（-/-）小鼠和涉及BMP诱导异位骨形成的系统检查了破骨细胞生成的要求。我们已经表明，成骨细胞也通过提供RANKL作用的关键微环境在破骨细胞生成中发挥重要作用。(4)用于破骨细胞特异性靶基因缺失的Cre-lox P系统的建立：我们成功地建立了RANK Cre小鼠。我们现在正在分析Cre重组酶在破骨细胞中的表达。(5)细胞周期调控基因转基因小鼠：我们正在推进破骨细胞生态位的实验，而不是生产周期调控基因转基因小鼠。(6)抗癌药物在骨疾病中的临床应用：我们已经证明紫杉烷类药物对骨转移癌的治疗具有有益作用。给小鼠注射抗癌药物5-氟尿嘧啶可引起骨髓抑制，但给予活性维生素D_3类似物后，QOP存活并分化为破骨细胞。我们已经表明，QOPs预先存在于破骨细胞生成的网站，成骨细胞在维持未分化状态的QOPs中发挥作用。我们发现c-Fos（-/-）小鼠没有破骨细胞龛。