A study on the molecular mechanism ofcytokine-mediated inhibition of osteoblast differentiation in rheumatoid arthritis

细胞因子介导抑制类风湿性关节炎成骨细胞分化的分子机制研究

• 批准号: 20591178
• 负责人: YAMAMURA Masahiro
• 金额: $ 2.58万
• 依托单位: Aichi Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20591178/
• 关键词: 関節リウマチ; 骨芽細胞; 炎症性サイトカイン; 骨形成蛋白質; 腫瘍壊死因子; Smad; 骨形成タンパク質

The cellular mechanism for cytokine-mediated inhibition of BMP-induced osteoblastic differentiation was investigated using mouse myoblast C2C12 cells. Osteoblast transformation of BMP-cultured C2C12 cells, and their Runx2/osteocalcin expression, ALP activity, and parathyroid hormone (PTH) responsiveness (cAMP production) were inhibited by TNF-α, but not by IL-1, IL-6, or IL-17. BMP-induced Smad1, 5, 8 phosphorylation in the cells was suppressed by TNF-α signaling, but inhibitory Smad6 gene activation was increased as determined by cDNA array. MAP kinase analysis showed that ERK1/ERK2 and SAPK/JNK phosphorylation were selectively activated in the cells with TNF-α. BMPs had no effect on TNF type 1 and 2 receptor-expression. Notably, SAPK/JNK inhibitors restored TNF-α inhibition of osteoblast differentiation, as demonstrated by Id-1-promoter activity as well as Runx2/osteocalcin mRNA levels. These results suggest that TNF-α may have a crucial role in BMP-induced osteogenic inhibition in the diseases such as rheumatoid arthritis, through its SAPK/JNK activation and Smad6 induction.

使用小鼠成肌细胞C2 C12细胞研究了苦参碱介导的抑制BMP诱导的成骨细胞分化的细胞机制。BMP培养的C2 C12细胞的成骨细胞转化、Runx 2/骨钙素表达、ALP活性和甲状旁腺激素（PTH）反应性（cAMP产生）均受到TNF-α的抑制，但不受IL-1、IL-6或IL-17的抑制。TNF-α抑制BMP诱导的Smad 1，5，8磷酸化，但抑制性Smad 6基因激活增加。MAP激酶分析显示，TNF-α可选择性激活ERK 1/ERK 2和SAPK/JNK磷酸化。BMP对TNF 1型和2型受体表达无影响。值得注意的是，SAPK/JNK抑制剂恢复了TNF-α对成骨细胞分化的抑制，如Id-1启动子活性以及Runx 2/骨钙素mRNA水平所证明的。这些结果提示TNF-α可能通过激活SAPK/JNK和诱导Smad 6在类风湿关节炎等疾病中对BMP诱导的成骨抑制起关键作用。

项目成果

Effect of infliximab on tumor necrosis factor-alpha-induced alterations in retinal microvascular endothelial cells and retinal pigment epithelial cells.

英夫利昔单抗对肿瘤坏死因子-α诱导的视网膜微血管内皮细胞和视网膜色素上皮细胞改变的影响。

• 发表时间: 2010
• 期刊: J Ocul Pharmacol Ther 26(6)
• 作者: Li H;Yoneda M;Takeyama M;Sugita I;Tsunekawa H;Yamada H;Watanabe D;Mukai T;Yamamura M;Iwaki M;Zako M.
• 通讯作者: Zako M.

Simvastatin antagonizes tumor necrosis factor-alpha inhibition of bone morphogenetic proteins-2-induced osteoblast differentiation by regulating Smad signaling and Ras/Rho-mitogen-activated protein kinase pathway.

辛伐他汀通过调节 Smad 信号传导和 Ras/Rho 丝裂原激活蛋白激酶途径，拮抗肿瘤坏死因子 α 对骨形态发生蛋白 2 诱导的成骨细胞分化的抑制。

• 发表时间: 2008
• 期刊: J Endocrinol 196
• 作者: Yamashita M;Otsuka F;Mukai T;Otani H;Inagaki K;Miyoshi T;Goto J;Yamamura M;Makino H
• 通讯作者: Makino H

ホームページ等。

主页等

ヒト間葉系幹細胞の骨芽細胞分化に及ぼす炎症性サイトカインの作用

炎症细胞因子对人间充质干细胞成骨细胞分化的影响

• 发表时间: 2009
• 作者: 向井知之;大塚文男;山村昌弘
• 通讯作者: 山村昌弘

Effects of TNFa, IL-1, and IL-17 0n osteoblast differentiation of human bone marrow-derived mesenchymal stem cells.

TNFa、IL-1 和 IL-17 0n 成骨细胞分化人骨髓间充质干细胞的影响。

• 发表时间: 2008
• 作者: Mukai M;Kawashima M;Yamamura M.
• 通讯作者: Yamamura M.