CCN family 2/connective tissue growth factor (CCN2/CTGF) regulates the expression of Vegf through Hif-1alpha expression in a chondrocytic cell line, HCS-2/8, under hypoxic condition.
CCN family 2/connective tissue growth factor (CCN2/CTGF) regulates the expression of Vegf through Hif-1alpha expression in a chondrocytic cell line, HCS-2/8, under hypoxic condition.
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DOI：
10.1016/j.bone.2008.08.125
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发表时间：
2009-01
期刊：
影响因子：
4.1
通讯作者：
Takigawa, Masaharu
中科院分区：
文献类型：
--
作者：
Nishida, Takashi;Kondo, Seiji;Maeda, Azusa;Kubota, Satoshi;Lyons, Karen M.;Takigawa, Masaharu
关键词：
血管内皮生长因子 (VEGF) 对于建立血管化和调节软骨细胞的发育和存活至关重要。我们已经证明 VEGF 调节 CCN2/结缔组织生长因子 (CCN2/CTGF) 的表达，CCN2/CTGF 是软骨发育和血管生成的重要介质，表明 CCN2 在 VEGF 下游发挥作用，并且 VEGF 功能部分由 CCN2 介导。另一方面，Ccn2突变体生长板的表型在肥大区表现出VEGF表达降低，表明Vegf表达也依赖于Ccn2表达。因此，我们使用人软骨细胞系 HCS-2/8 研究了 CCN2 诱导 VEGF 的分子机制。与常氧条件下培养的细胞相比，HCS-2/8 细胞的缺氧刺激 (5% O2) 在 6 小时内使 VEGF mRNA 水平增加约 8 倍。此外，转染Ccn2表达质粒的HCS-2/8细胞在缺氧条件下VEGF表达进一步上调。重组 CCN2 (rCCN2) 刺激可增加缺氧诱导因子 (HIF)-1α mRNA 和蛋白质水平。此外，当细胞受到rCCN2刺激时，HCS-2/8中包含HIF-1结合位点的VEGF启动子的活性增加。这些结果表明CCN2通过促进HIF-1α活性在转录水平上调节VEGF的表达。事实上，在野生型小鼠的增殖和肥大前软骨细胞的细胞核中检测到了 HIF-1α，而在体内的 Ccn2 突变软骨细胞中未检测到 HIF-1α。因此，从 CCN2 到 VEGF 的这种激活级联可能在软骨细胞的发育和存活中发挥关键作用。
Vascular endothelial growth factor (VEGF) is essential for establishing vascularization and regulating chondrocyte development and survival. We have demonstrated that VEGF regulates the expression of CCN2/connective tissue growth factor (CCN2/CTGF) an essential mediator of cartilage development and angiogenesis, suggesting that CCN2 functions in down-stream of VEGF, and that VEGF function is mediated in part by CCN2. On the other hand, the phenotype of Ccn2 mutant growth plates, which exhibit decreased expression of VEGF in the hypertrophic zone, indicates that Vegf expression is dependent on Ccn2 expression as well. Therefore, we investigated the molecular mechanisms underlying the induction of VEGF by CCN2 using a human chondrocytic cell line, HCS-2/8. Hypoxic stimulation (5% O2) of HCS-2/8 cells increased VEGF mRNA levels by ~8 fold within 6 h as compared with the cells cultured under normoxia. In addition, VEGF expression was further up-regulated under hypoxia in HCS-2/8 cells transfected with a Ccn2 expression plasmid. Hypoxia-inducible factor (HIF)-1α mRNA and protein levels were increased by stimulation with recombinant CCN2 (rCCN2). Furthermore, the activity of a VEGF promoter that contained a HIF-1 binding site was increased in HCS-2/8, when the cells were stimulated by rCCN2. These results suggest that CCN2 regulates the expression of VEGF at a transcriptional level by promoting HIF-1α activity. In fact, HIF-1α was detected in the nuclei of proliferative and pre-hypertrophic chondrocytes of wild-type mice, whereas it was not detected in Ccn2 mutant chondrocytes in vivo. This activation cascade from CCN2 to VEGF may therefore play a critical role in chondrocyte development and survival.
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影响因子：
4.8
作者：
Inoki, I;Shiomi, T;Okada, Y
通讯作者：
Okada, Y
DOI：
10.1006/bbrc.1998.8895
发表时间：
1998-06-29
影响因子：
3.1
作者：
Nishida, T;Nakanishi, T;Takigawa, M
通讯作者：
Takigawa, M
影响因子：
4.6
作者：
Ivkovic, S;Yoon, BS;Lyons, KM
通讯作者：
Lyons, KM
影响因子：
6.2
作者：
Nishida, T;Kubota, S;Takigawa, M
通讯作者：
Takigawa, M
DOI：
10.1142/9781860946899_0001
发表时间：
2005-01-01
期刊：
CCN PROTEINS: A NEW FAMILY OF CELL GROWTH AND DIFFERENTIATION REGULATORS
影响因子：
--
作者：
Perbal, Bernard;Takigawa, Masaharu
通讯作者：
Takigawa, Masaharu