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Study on signal transduction in osteoclastogenesis for the development of anti-osteoporosis drugs.

破骨细胞生成信号转导研究，用于抗骨质疏松药物的开发。

基本信息

批准号：
11557139
负责人：
TAKAHASHI Naoyuki
金额：
$ 8.64万
依托单位：
Showa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11557139/
关键词：
Osteoclast Osteoblast Inflammatory cytokines Calcium BMP RANKL OPG Osteoporosis ODF RANK TNFα IL-1 細胞内Ca

项目摘要

Inhibition of signal transduction for osteoclastogenesis is thought to provide important information for development of anti-osteoporosis drugs. We have succeeded in molecular cloning of an essential factor for osteoclastogenesis, RANKL, which is expressed as a membrane associated factor in osteoblasts in response to many bone-resorbing factors. Using culture systems for osteoclast formation, we have studied signal transduction for osteoclastogenesis including RANK-RANKL signaling. The findings obtained from the study are as follows. (1) TNFα stimulated osteoclastogenesis in bone marrow-derived macrophage cultures in the presence of M-CSF.(2) SaOS-4/3, a subclone of the human osteosarcoma cell line SaOS-2, established by transfecting the human PTH/PTHrP receptor cDNA, supported osteoclast formation in response to PTH in co-culture with mouse bone marrow cells. Expression of mRNAs for RANKL and M-CSF by SaOS-4/3 cells was up-regulated in response to PTH.Both factors were expressed as membrane-associated factors. (3) Ionomycin and A23187 stimulated osteoclast formation in mouse co-cultures of bone marrow cells and osteoblasts. We also found that PMA, an activator of protein kinase C, stimulated osteoclast formation in the co-culture though up-regulation of RANKL expression in osteoblasts. (4) BMP-2 markedly enhanced osteoclast differentiation induced by RANKL and M-CSF.Addition of a soluble form of BMP receptor type-IA to the culture inhibited not only osteoclast formation induced by RANKL and BMP-2, but also the basal osteoclast formation supported by RANKL alone. Both bone marrow macrophages and mature osteoclasts expressed BMP-2 and BMP receptor type IA mRNAs. These findings provide important information for the development of anti-osteoporosis drugs.

抑制破骨细胞生成的信号转导为开发抗骨质疏松药物提供了重要信息。我们已经成功地在分子克隆破骨细胞生成的一个必要因素，RANKL，这是作为一个膜相关因子在成骨细胞中的许多骨吸收因子的反应。使用破骨细胞形成的培养系统，我们研究了破骨细胞生成的信号转导，包括RANK-RANKL信号转导。研究结果如下。(1)在M-CSF存在下，TNFα刺激骨髓源性巨噬细胞培养物中的破骨细胞生成。(2)SaOS-4/3是人骨肉瘤细胞系SaOS-2的亚克隆，通过克隆人PTH/PTHrP受体cDNA而建立，在与小鼠骨髓细胞共培养时支持破骨细胞响应PTH的形成。PTH可上调SaOS-4/3细胞RANKL和M-CSF的mRNA表达，这两种因子均以膜相关因子的形式表达。(3)离子霉素和A23187刺激小鼠骨髓细胞和成骨细胞共培养物中破骨细胞的形成。我们还发现，PMA，蛋白激酶C的激活剂，刺激破骨细胞的形成，在共培养通过上调RANKL在成骨细胞的表达。(4)BMP-2能显著促进RANKL和M-CSF诱导的破骨细胞分化，加入可溶性IA型BMP受体不仅能抑制RANKL和BMP-2诱导的破骨细胞形成，还能抑制RANKL单独支持的破骨细胞基础形成。骨髓巨噬细胞和成熟破骨细胞均表达BMP-2和BMP受体IA型mRNA。这些发现为抗骨质疏松药物的开发提供了重要信息。