The Regulation of Bone-Remodeling by Signals mediated by Phosphorylation

磷酸化介导的信号对骨重建的调节

• 批准号: 11307041
• 负责人: YONEDA Toshiyuki
• 金额: $ 24.16万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11307041/
• 关键词: Osteoclast; Osteoblast; Adipocytes; NF-kB; JNK; BMP2; Cbfa1; Smad; Src; アデノウイルス; Csk

(1) Role of C/EBP beta in the differentiation of mesenchymal stem cells into osteoblasts and adipocytesWe found that C/EBP beta is able to induce the differentiation of mesenchymal stem cells into not only adipocytes but also osteoblasts. In addition, an isoform of C/EBP beta, LIP, blocks the adipogenesis in a dominant-negative fashion, but exhibits osteogenic action as a co-factor for Cbfa1. Our data provide the new insight into the understanding the molecular mechanisms that determine the direction of mesenchymal stem cells in bone.(2) The role of JNK/c-Jun signaling in osteoclast differentiationTreatment of RANK ligand (RANKL) promoted the osteoclastic differentiation of mouse monocytic cell line RAW264 cells. RANKL also activated JNK, c-Jun and transcription of AP-1. Overexpression of dominant negative JNK or c-Jun markedly inhibited the formation of osteoclasts by RANKL stimulation in RAW264 cells by blocking the activation of JNK or c-Jun signaling. The data suggest the crucial role of JNK/c-Jun signaling in the osteoclast differentiation by RANKL.(3) Suppressive effects on osteoblastic differentiation and Induction of its apoptosis by TNF-alphaWe observed that TNF suppressed the osteoblastic differentiation of mesenchymal stem cells and promoted the apoptosis of mature osteoblasts. Blockade of NF-kB signaling by overexpression of mutant l-kB alpha profoundly inhibited the effect of TNF on osteoblastic differentiation of undifferentiated mesenchymal cells. In contrast, overexpression of the mutant l-kB alpha accelerated the apoptosis induced by TNF. The data suggest that TNF suppresses osteoblastic differentiation of mesenchymal cells and accelerated the apoptosis by regulating NF-kB signaling.

(1)C/EBPβ在间充质干细胞向成骨细胞和脂肪细胞分化中的作用我们发现C/EBPβ不仅能够诱导间充质干细胞向脂肪细胞分化，而且能够诱导向成骨细胞分化。此外，C/EBP beta 的同种型 LIP 以显性负性方式阻断脂肪生成，但作为 Cbfa1 的辅助因子表现出成骨作用。我们的数据为理解决定骨中间充质干细胞方向的分子机制提供了新的见解。(2)JNK/c-Jun信号在破骨细胞分化中的作用RANK配体(RANKL)的处理促进了小鼠单核细胞系RAW264细胞的破骨细胞分化。 RANKL 还激活 JNK、c-Jun 和 AP-1 的转录。显性失活 JNK 或 c-Jun 的过表达通过阻断 JNK 或 c-Jun 信号传导的激活，显着抑制 RAW264 细胞中 RANKL 刺激的破骨细胞形成。这些数据表明JNK/c-Jun信号在RANKL的破骨细胞分化中发挥着至关重要的作用。(3)TNF-α对成骨细胞分化的抑制作用及其诱导其凋亡我们观察到TNF抑制间充质干细胞的成骨细胞分化并促进成熟成骨细胞的凋亡。通过突变型 l-kB α 的过度表达来阻断 NF-kB 信号传导可显着抑制 TNF 对未分化间充质细胞的成骨细胞分化的影响。相反，突变体l-kB α的过度表达加速了TNF诱导的细胞凋亡。数据表明TNF通过调节NF-kB信号传导抑制间充质细胞的成骨细胞分化并加速细胞凋亡。

项目成果

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