权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

A study of cross-talk between the expression mechanisms of osteoclast differentiation factor (ODF) and osteoclastogenesis inhibitory factor (OCIF)

破骨细胞分化因子（ODF）与破骨细胞生成抑制因子（OCIF）表达机制的交叉研究

基本信息

批准号：
15390465
负责人：
SUDA Tatsuo
金额：
$ 7.62万
依托单位：
Saitama Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
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

项目摘要

Bone is a dynamic tissue that is formed and remodeled by continuously occurring bone formation and resorption. Osteoblasts are involved not only in bone formation, but also in bone resorption via inducing osteoclast differentiation factor (ODF)/receptor activator of NF-kB ligand (RANKL) and its antagonist, osteoclastogenesis inhibitory factor OCIF)/osteoprotegerin (OPG) in osteoblasts. In the present study, we examined a potential regulatory mechanism of RANKL and OPG expression by bone-resorbing hormones in osteoblasts. Both 1,25(OH)_2D_3 and parathyroid hormone (PTH) induced RANKL mRNA expression and inhibited OPG mRNA expression. These effects of PTH reached a peak within 3 h, then sharply decreased thereafter, whereas those of 1,25(OH)_2D_3 gradually increased up to 10 h and were kept until 24 h. The effects of 1,25(OH)_2D_3 were blocked by adding cychloheximide but not MAP kinase inhibitors, suggesting that dc novo protein synthesis is essential for the l,25(OH)_2D_3 effects. Target genes of 1,25(OH)_2D_3 were analyzed by microarray analysis. Vitamin D receptor (VDR), interleukin 4 receptor a (IL4Ra) and a RNA helicase (Ddx21), were up-regulated more than 2 fold, and serum/glucocorticoid- regulated kinase (Sgk) was down-regulated more than 0.5 fold in osteoblastic cells by 1,25(OH)_2D_3. Transient over-expression of VDR, IL4Ra or Ddx21 in osteoblasts decreased the levels of RANKL mRNA induced by 1,25(OH)_2D_3. VDR increased the basal level of RANKL mRNA. However, none of them affected OPG mRNA levels irrespective of the presence and absence of 1,25(OH)_2D_3. Taken together, these results suggest that VDR, IL4Ra and Ddx21 are involved in the RANKL expression induced by 1,25(OH)_2D_3. Different transcription factors may regulate mRNA expression of RANKL and OPG in response to 1,25(OH)_2D_3.

骨是一种动态组织，通过不断发生的骨形成和吸收而形成和重塑。成骨细胞不仅参与骨形成，还通过在成骨细胞中诱导破骨细胞分化因子（ODF）/NF-kB配体受体激活剂（RANKL）及其拮抗剂破骨细胞生成抑制因子（OCIF）/骨保护素（OPG）参与骨吸收。在本研究中，我们研究了成骨细胞中骨吸收激素对 RANKL 和 OPG 表达的潜在调节机制。 1,25(OH)_2D_3 和甲状旁腺激素 (PTH) 均诱导 RANKL mRNA 表达并抑制 OPG mRNA 表达。 PTH的这些作用在3小时内达到峰值，然后急剧下降，而1,25(OH)_2D_3的作用在10小时内逐渐增加，并保持到24小时。 1,25(OH)_2D_3 的作用可通过添加环己酰亚胺而非 MAP 激酶抑制剂来阻断，这表明 dc novo 蛋白质合成对于 1,25(OH)_2D_3 作用至关重要。通过微阵列分析对1,25(OH)_2D_3的靶基因进行分析。 1,25(OH)_2D_3 在成骨细胞中维生素 D 受体 (VDR)、白细胞介素 4 受体 a (IL4Ra) 和 RNA 解旋酶 (Ddx21) 上调超过 2 倍，血清/糖皮质激素调节激酶 (Sgk) 下调超过 0.5 倍。成骨细胞中 VDR、IL4Ra 或 Ddx21 的瞬时过表达降低了 1,25(OH)_2D_3 诱导的 RANKL mRNA 水平。 VDR 增加了 RANKL mRNA 的基础水平。然而，无论 1,25(OH)_2D_3 是否存在，它们都不影响 OPG mRNA 水平。综上所述，这些结果表明 VDR、IL4Ra 和 Ddx21 参与 1,25(OH)_2D_3 诱导的 RANKL 表达。不同的转录因子可能响应 1,25(OH)_2D_3 调节 RANKL 和 OPG 的 mRNA 表达。