Regulatory Mechanism of RANK Gene Expression during Osteoclastic Differentiation of Bone Marrow Macrophage/Monocyte Lineage

骨髓巨噬细胞/单核细胞谱系破骨分化过程中RANK基因表达的调控机制

• 批准号: 21590419
• 负责人: KITAZAWA Riko
• 金额: $ 2.83万
• 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: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21590419/
• 关键词: 破骨細胞; RANK; 遺伝子プロモータ; 転写因子; RANKL; 造血細胞

Receptor activator of NF-kappaB(RANK) expressed on osteoclasts and their precursors is a receptor for RANK Ligand(RANKL). RANKL-RANK interaction induces genes essential for the differentiation of osteoclasts through the binding of NFATc1 to target gene promoters. We have cloned a 6-kb fragment containing the 5'-flanking region of the mouse RANK gene and have analyzed the binding elements such as PU. 1(-480), and MITF(-100). Here, we showed the regulatory mechanism of RANK gene transcription through the NFAT(-370) and CRE/AP-1 binding sites(-240). Furthermore, we have identified a novel alternative splicing variant of mouse RANK gene that contains a new intervening exon between exon 1 and exon 2 of mouse full-length RANK mRNA, and shown that variant RANK is a novel osteoclast suppressor that reduces the number of RANKL-induced mature osteoclasts mainly by negating the anti-apoptotic effect of RANKL.

NF-kappaB受体激活因子（Receptor activator of NF-kappaB， RANK）表达于破骨细胞及其前体，是一种RANK配体受体（RANKL）。RANKL-RANK相互作用通过NFATc1结合靶基因启动子诱导破骨细胞分化所必需的基因。我们克隆了一个含有小鼠RANK基因5'-侧翼区域的6kb片段，并分析了其结合元件如PU。1（-480）和MITF（-100）。在这里，我们通过NFAT（-370）和CRE/AP-1结合位点（-240）展示了RANK基因转录的调控机制。此外，我们发现了一种新的小鼠RANK基因的选择性剪接变体，该变体在小鼠全长RANK mRNA的外显子1和外显子2之间含有一个新的干预外显子，并表明RANK变体是一种新的破骨细胞抑制因子，主要通过否定RANKL的抗凋亡作用来减少RANKL诱导的成熟破骨细胞的数量。

项目成果

Derepression of Mouse SFRP-4 Gene Expression by Oxidative Stress : A Plausible Mechanism Leading to Low-turnover Osteoporosis in Diabetes and Senescence.

氧化应激对小鼠 SFRP-4 基因表达的去抑制：导致糖尿病和衰老中低周转骨质疏松症的合理机制。

• 发表时间: 2010
• 作者: Mori K.;et al.
• 通讯作者: et al.

Oxidative DNA Damage to Methylated CpG Located at Five Bases Upstream of TATA-box Restores Suppressed sFRP-4 Gene Expression : Proposal of A Unique Mechanism towards Diabetic Osteoporosis.

位于 TATA-box 上游五个碱基的甲基化 CpG 的氧化 DNA 损伤可恢复受抑制的 sFRP-4 基因表达：针对糖尿病骨质疏松症的独特机制的提议。

• 发表时间: 2009
• 作者: Mori K;et al.
• 通讯作者: et al.

Oxidative and Nitrosative Stress and Progression of Diabetic Nephropathy in Type 2 Diabetes

• DOI: 10.1159/000297290
• 发表时间: 2010-01-01
• 期刊: AMERICAN JOURNAL OF NEPHROLOGY
• 影响因子: 4.2
• 作者: Fujii, Hideki;Kono, Keiji;Fukagawa, Masafumi
• 通讯作者: Fukagawa, Masafumi

Thioredoxin-1 overexpression in transgenic mice attenuates streptozotocin-induced diabetic osteopenia

转基因小鼠中硫氧还蛋白-1 过度表达可减轻链脲佐菌素诱导的糖尿病骨质减少

• 发表时间: 2009
• 期刊: Bone 44
• 作者: Hamada Y.;et al.
• 通讯作者: et al.

病理と臨床29巻臨時増刊号「病理診断に役立つ分子生物学」第1部-4 DNAシークエンス

病理学与临床第 29 卷特刊“对病理诊断有用的分子生物学”第 1-4 部分 DNA 序列

• 发表时间: 2011
• 作者: 北澤荘平;森清;近藤武史;北澤理子
• 通讯作者: 北澤理子