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A STUDY ON THE CONTROL OF BONE DESTRUCTION USING OSTEOCLAST DIFFERENTIATION FACTOR AS A TARGET

以破骨细胞分化因子为靶点控制骨破坏的研究

基本信息

批准号：
13480205
负责人：
YASUDA Hisataka
金额：
$ 9.6万
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：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

Osteoclast differentiation factor, RANKL, is a membrane-bound protein. It is thought that RANKL functions as a membrane-form because osteoclast differentiation requires the interaction between osteoclast progenitors and osteoblasts. Although it is reported that soluble RANKL (sRANKL) is produced by activated T -cells and sRANKL is involved in the inflammatory bone destruction, the function of sRANKL is unknown. We generated transgenic (TG) mice overexpressing sRANKL to investigate the physiological roles of sRANKL. The TG mice as well as osteoclastogenesis inhibitory factor, osteoprotegerin (OPG)-deficient (KO) mice exhibited severe osteoporosis. These results suggest that overexpresssion of sRANKL in vivo due to pathological conditions such as inflammation results in bone destruction. The number of osteoclasts increases in both sRANKL-TG nice and OPG-KO mice by the similar mechanism that the increase of the ratio of RANKL and OPG in bone causes osteoclast differentiation. The coupling between bone formation and bone resorption observed in OPG-KO mice was not observed in sRANKL-TG mice. The detailed comparison of the phenotypes of the two types of mice will facilitate the identification of the coupling mechanism and coupling factors involved in the process.Runx2 is the transcription factor essential for osteoblast differentiation. Runx2-KO mice have cartridge but lack osteoblasts and bone. Runx2-KO mice almost lack osteoclasts probably due to the absence of osteoblasts. We mated Runx2-KO mice and sRANKL-TG mice to investigate the mechanism by which Runx2-KO mice lack osteoclasts. The number of osteoclasts increased in Runx2-KO/sRANKL-TG mice, suggesting that the osteoclast differentiation in Runx2-KO/sRANKL-TG mice was restored by sRANKL and that osteoblasts differentiated by Runx2 was the source of RANKL.

破骨细胞分化因子RANKL是一种膜结合蛋白。RANKL被认为是一种膜形式，因为破骨细胞的分化需要破骨细胞前体和成骨细胞之间的相互作用。尽管有报道称可溶性RANKL(SRANKL)是由活化的T细胞产生的，sRANKL参与了炎症性骨破坏，但sRANKL的功能尚不清楚。我们建立了高表达sRANKL的转基因(TG)小鼠，以研究sRANKL的生理作用。TG小鼠以及破骨细胞生成抑制因子、骨保护素(OPG)缺陷(KO)小鼠表现出严重的骨质疏松。这些结果表明，由于炎症等病理条件，sRANKL在体内的过度表达会导致骨破坏。SRANKL-TGNICE和OPG-KO小鼠破骨细胞数量均增加，其机制与骨中RANKL/OPG比例增加导致破骨细胞分化相似。在OPG-KO小鼠中观察到的骨形成和骨吸收之间的偶联在sRANKL-TG小鼠中没有观察到。对两种类型小鼠的表型进行详细的比较，将有助于确定偶联机制和参与这一过程的偶联因素。Runx2是成骨细胞分化所必需的转录因子。Runx2-KO小鼠有骨盒，但缺乏成骨细胞和骨。Runx2-KO小鼠几乎缺乏破骨细胞，可能是由于缺乏成骨细胞。我们用Runx2-KO小鼠和sRANKL-TG小鼠交配，以探讨Runx2-KO小鼠缺乏破骨细胞的机制。Runx2-KO/sRANKL-TG小鼠破骨细胞数量增加，提示sRANKL可恢复Runx2-KO/sRANKL-TG小鼠破骨细胞分化，Runx2分化的成骨细胞是RANKL的来源。