Nuclear factor E2 p45-related factor 2 negatively regulates chondrogenesis
Nuclear factor E2 p45-related factor 2 negatively regulates chondrogenesis
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DOI：
10.1016/j.bone.2006.08.016
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发表时间：
2007-02-01
期刊：
影响因子：
4.1
通讯作者：
Yoneda, Yukio
中科院分区：
文献类型：
--
作者：
Hinoi, Eiichi;Takarada, Takeshi;Yoneda, Yukio
转录因子核因子E2 p45相关因子2（Nrf2）与小肌肉腱膜纤维肉瘤（Maf）蛋白形成异二聚体，用于选择性识别靶基因上的抗氧化反应元件，随后调节不同组织中II期解毒酶和氧化应激诱导蛋白的基因表达。在本研究中，我们研究了Nrf2在软骨细胞分化的调节中的作用以及Nrf2在软骨中的表达模式。在E15.5的胚胎小鼠胫骨中，Nrf2 mRNA表达仅限于增殖和前肥大软骨细胞，在早期和晚期肥大软骨细胞中几乎没有信号表达X型胶原和骨桥蛋白。在出生后1天的新生小鼠胫骨原位杂交分析，相比之下，Nrf2表达在所有软骨细胞层除了成骨细胞连接到松质骨。此外，在软骨形成前细胞系ATDC 5细胞中，还证实了Nrf2 mRNA的表达以及Kelch样ECH相关蛋白1和小Maf蛋白的mRNA表达。在ATDC 5细胞中，Nrf2稳定转染，显着抑制碱性磷酸酶的分化依赖性诱导和阿辛蓝染色强度增加。此外，Nrf2的稳定过表达显著降低了几种软骨细胞分化标志物如II型胶原、X型胶原和骨桥蛋白的mRNA表达。这些数据表明，Nrf2可能是一个负调节器的细胞分化成熟的软骨细胞。(c)2006爱思唯尔公司All rights reserved.
The transcription factor nuclear factor E2 p45-related factor 2 (Nrf2) forms heterodimers with small musculoaponeurotic fibrosarcoma (Maf) proteins for the selective recognition of the antioxidant responsive element on target genes, followed by the regulation of gene expression of phase II detoxifying enzymes as well as oxidative-stress-inducible proteins in different tissues. In the present study, we investigated the role of Nrf2 in the regulation of chondrocyte differentiation as well as the expression pattern of Nrf2 in cartilage. In tibia from embryonic mice at E15.5, Nrf2 mRNA expression was restricted to both proliferating and pre-hypertrophic chondrocytes, with few signals in early and late hypertrophic chondrocytes expressing both type X collagen and osteopontin. On in situ hybridization analysis of tibia from neonatal mice at 1 day after birth, by contrast, Nrf2 was expressed in all chondrocytic layers in addition to osteoblasts attached to cancellous bone. In pre-chondrogenic cell line ATDC5 cells, furthermore, expression of Nrf2 mRNA was also confirmed together with mRNA expression of the Kelch-like ECH associating protein 1 and small Maf proteins. In ATDC5 cells stably transfected with Nrf2, significant inhibition was seen in the differentiation-dependent induction of alkaline phosphatase and increase in the Alcian blue staining intensity. Furthermore, stable overexpression of Nrf2 significantly decreased mRNA expression of several chondrocyte differentiation markers such as type II collagen, type X collagen and osteopontin. These data suggest that Nrf2 may be a negative regulator of the cellular differentiation toward maturation in chondrocytes. (c) 2006 Elsevier Inc. All rights reserved.