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）在破骨细胞祖细胞中对细胞周期的体外分析：我们已经表明，在破骨细胞前体进行进展后细胞周期的进展和戒断是对骨诱导的破骨造成的骨化的两个顺序事件。体外前体。体内实验表明，在RANKL缺陷小鼠的成骨细胞附近检测到表达C-FMS和等级但未表达KI67的单核细胞。（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诱导的涉及BMP诱导的造成造成骨骼骨形成的小鼠（ - ）小鼠（ - ）小鼠（ - ）小鼠（ - / - ）小鼠检查了破骨细胞生成的要求。我们已经表明，成骨细胞还通过为RANKL作用的关键微环境提供关键的微环境，在整骨构成中起重要作用。（4）建立Cre-lox P系统，用于靶基因的破骨细胞特异性缺失：我们已经成功地建立了等级CRE小鼠。（5）细胞周期调节基因的转基因小鼠的CRE重组酶表达。（5）我们正在推进对破骨细胞菌群的实验，稳定于周期调节性基因转基因小鼠的产生。癌症。给小鼠的抗癌药物5-氟尿嘧啶的给药诱导了骨髓抑制，但是响应于给予这些小鼠的活性维生素D_3类似物，QOPS存活并分化为破骨细胞。我们已经表明，QOP在破骨细胞生成部位预先存在，成骨细胞在未分化状态下的群体维持中起着作用。我们发现C-Fos（ - / - ）小鼠没有破骨细胞生态位。