Elucidation of the mechanism of aggrecan degradation and epigenetic regulation of aggrecanase expression in osteoarthritic cartilage

阐明骨关节炎软骨中聚集蛋白聚糖降解的机制和聚集蛋白聚糖酶表达的表观遗传调控

• 批准号: 20591780
• 负责人: NISHIDA Keiichiro
• 金额: $ 2.66万
• 依托单位: Okayama 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-20591780/
• 关键词: 変形性関節症; 軟骨破壊; アグリカナーゼ; メカニカルストレス; mechanical stress; chondrocyte; RUNX2; MMP-13; ADAMTS-5; interleukin-4; ヒストン脱アセチル化酵素阻害剤; ピストン脱アセチル化酵素阻害剤

We investigated the mechanism of mechanical stress-induced expression and regulation of aggrecanases and examined the role of runt-related transcription factor 2 (RUNX-2) in chondrocyte-like cells. A uni-axial cyclic tensile strain (CTS) (0.5 Hz, 10% stretch) induced expression of RUNX-2, MMP-13, ADAMTS-4, -5, and -9 by SW1353 cells. Overexpression of RUNX-2 up-regulated expression of MMP-13 and ADAMTS-5, whereas RUNX-2 siRNA resulted in significant downregulation of mechanically-induced MMP-13 and ADAMTS-5 expression. CTS induced activation of p38 MAPK, and CTS induction of RUNX-2, MMP-13 and ADAMTS-5 mRNA was down-regulated by the selective p38 MAPK inhibitor SB203580 but not by the p44/42 MAPK inhibitor U0126, or the JNK MAPK inhibitor JNK inhibitor II. These results suggested that RUNX-2 might have a role as a key downstream mediator of p38's ability to regulate mechanical stress-induced MMP-13 and ADAMTS-5 expression. Furthermore, histone deacetylase (HDAC) inhibitor, trichostatin A and MS-275 downregulated the expression of mechanically-induced RUNX-2 and ADAMTS-5. The epigenetic regulation of RUNX-2 transcriptional factor by HDAC inhibitor might be beneficial for the suppression of cartilage degeneration of early phase of osteoarthritis.

我们研究了机械应力诱导的聚集蛋白聚糖酶表达和调节的机制，并研究了软骨细胞样细胞中runt相关转录因子2（RUNX-2）的作用。单轴循环拉伸应变（CTS）（0.5 Hz，10%拉伸）诱导SW 1353细胞表达RUNX-2、MMP-13、ADAMTS-4、-5和-9。RUNX-2的过表达上调MMP-13和ADAMTS-5的表达，而RUNX-2 siRNA导致机械诱导的MMP-13和ADAMTS-5的表达显著下调。CTS可诱导p38 MAPK的激活，而选择性p38 MAPK抑制剂SB 203580可下调CTS诱导的RUNX-2、MMP-13和ADAMTS-5 mRNA的表达，而p44/42 MAPK抑制剂U 0126或JNK MAPK抑制剂JNK inhibitor II则不能下调CTS诱导的RUNX-2、MMP-13和ADAMTS-5 mRNA的表达。这些结果表明，RUNX-2可能作为p38调节机械应力诱导的MMP-13和ADAMTS-5表达能力的关键下游介质发挥作用。此外，组蛋白去乙酰化酶（HDAC）抑制剂，抑制素A和MS-275下调机械诱导的RUNX-2和ADAMTS-5的表达。HDAC抑制剂对RUNX-2转录因子的表观遗传调控可能有助于抑制骨关节炎早期软骨退变。

项目成果

メカニカルストレスと軟骨破壊

机械应力和软骨破坏

• 发表时间: 2009
• 期刊: 臨床リウマチ 21
• 作者: 田中政巳;横見出;渡辺実;佐藤均;五十嵐恒雄;関あずさ;小林真一;西田圭一郎
• 通讯作者: 西田圭一郎

軟骨細胞様細胞における力学的負荷誘導性のRunx2およびMMPべ3, ADAMTS-5の発現

软骨细胞样细胞中机械负荷诱导的 Runx2、MMPbe3 和 ADAMTS-5 表达

• 发表时间: 2009
• 作者: 鉄永智紀;西田圭一郎;尾崎敏文
• 通讯作者: 尾崎敏文

Intra-articular injection of interleukin-4 decreases nitric oxide production by ehondrocytes and ameliorates subsequent destruction of cartilage in instability-induced osteoarthritis in rat knee joints

关节内注射白细胞介素4可减少软骨细胞产生一氧化氮，并改善大鼠膝关节不稳定性诱发的骨关节炎中随后的软骨破坏

• 发表时间: 2008
• 期刊: Osteoarthritis and Cartilage 16
• 作者: Yorimitsu M;Nishida K;Shimizu A;Doi H;Miyazawa s;Komiyama T;Nasu Y. Yoshida A;Watanabe S Ozaki T
• 通讯作者: Watanabe S Ozaki T

Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen anti body-induced arthritis mouse model

• DOI: 10.1016/j.joca.2007.10.014
• 发表时间: 2008-06-01
• 期刊: OSTEOARTHRITIS AND CARTILAGE
• 影响因子: 7
• 作者: Nasu, Y.;Nishida, K.;Ozaki, T.
• 通讯作者: Ozaki, T.

Up-regulation of Runx2 and proteolytic enzymes by cyclic tensile stress in chondrocyte-like cells

软骨细胞样细胞中循环拉应力上调 Runx2 和蛋白水解酶

• 发表时间: 2008
• 期刊: Modern Rheumatology 18
• 作者: T. Tetsunaga;K. Nishida;S. Hirohata;K. Naruse;T. Ozaki
• 通讯作者: T. Ozaki