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Research of the signals of osteoblast differentiation and mineralization including menin and Smad

Menin、Smad等成骨细胞分化和矿化信号的研究

基本信息

批准号：
15590977
负责人：
KAJI Hirohi
金额：
$ 1.86万
依托单位：
Kobe University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590977/
关键词：
TGF-beta Menin Smad osteoblast JunD bone formation glucocorticoid parathyroid hormone 分化 TGFβ Smad3 アポトーシス

项目摘要

We previously revealed that menin, a product of multiple endocrine neoplasia type I gene, is required for the early differentiation of osteoblast and inhibits it at later stage. Moreover, we proposed that Smad3, TGF-beta-specific signaling molecule, is important for bone formation. On the other hand, parathyroid hormone (PTH) is one of most potent bone formation stimulating agents. However, the mechanism, by which PTH stimulates bone formation, remains unknown. In the present study, we demonstrated that PTH-Smad3 axis exerts anti-apoptotic effects in osteoblasts and might be involved in the bone anabolic action of PTH. In addition, dexamethasone, a glucocorticoid analogue, inhibits alkaline phosphatase activity and type I collagen expression, presumably by suppressing Smad3-induced transcriptional activity but not by modulating Smad3 expression in osteoblasts. This evidence might be partially related to the inhibitory action of glucocorticoid on osteoblastic bone formation. On the other hand, we demonstrated that menin interacts physically and functionally with Runx2 as well as Smad 1/5 in uncommited mesenchymal stem cells, but not in well differentiated osteoblasts. In osteoblasts, the interaction of menin and TGF-beta/Smad3 pathway negatively regulates the BMP-2/Smad1/5- and Runx2-induced transcriptional activities leading to inhibition of late stage differentiation. Moreover, menin suppresses osteoblast maturation, in part, by inhibiting the differentiation actions of JunD, AP-1 factor.

我们之前发现menin是多发性内分泌瘤I型基因的产物，是成骨细胞早期分化所必需的，并在后期抑制成骨细胞的分化。此外，我们提出tgf - β特异性信号分子Smad3对骨形成很重要。另一方面，甲状旁腺激素（PTH）是最有效的骨形成刺激剂之一。然而，甲状旁腺激素刺激骨形成的机制尚不清楚。在本研究中，我们发现PTH- smad3轴在成骨细胞中具有抗凋亡作用，并可能参与了PTH的骨合成代谢作用。此外，糖皮质激素类似物地塞米松抑制碱性磷酸酶活性和I型胶原表达，可能是通过抑制Smad3诱导的转录活性，而不是通过调节Smad3在成骨细胞中的表达。这可能与糖皮质激素对成骨细胞成骨形成的抑制作用有关。另一方面，我们证明menin在未分化的间充质干细胞中与Runx2和Smad 1/5在物理和功能上相互作用，但在分化良好的成骨细胞中则没有。在成骨细胞中，menin和tgf - β /Smad3通路的相互作用负向调节BMP-2/Smad1/5-和runx2诱导的转录活性，从而抑制后期分化。此外，menin抑制成骨细胞成熟，部分是通过抑制JunD， AP-1因子的分化作用。