The relation of Wnt/beta-catenin signaling to osteoarthritis progression has been revealed with little information on the underlying molecular mechanism. In this study we found overexpression of Lef1 in cartilage tissue of osteoarthritic patients and elucidated molecular mechanism of NF-kappaB-mediated Lef1 gene regulation in chondrocytes. Treatment of IL-1beta augmented Lef1 upregulation and nuclear translocation of NF-kappaB in chondrocytes. Under IL-1beta signaling, treatment of NF-kappaB nuclear translocation inhibitor SN-50 reduced Lef1 expression. A conserved NF-kappaB-binding site between mouse and human was selected through bioinformatic analysis and mapped at the 14 kb upstream of Lef1 transcription initiation site. NF-kappaB binding to the site was confirmed by chromatin immunoprecipitation assay. Lef1 expression was synergistically upregulated by interactions of NF-kappaB with Lef1/beta-catenin in chondrocytes. Our results suggest a pivotal role of NF-kappaB in Lef1 expression in arthritic chondrocytes or cartilage degeneration.

译文

Wnt/β-catenin信号与骨关节炎进展的关系已被揭示,但有关潜在分子机制的信息很少。在这项研究中,我们发现了骨关节炎患者软骨组织中Lef1的过表达,并阐明了NF-κ b介导的软骨细胞中Lef1基因调控的分子机制。IL-1beta治疗可增强软骨细胞中NF-κ b的Lef1上调和核移位。在IL-1beta信号下,NF-κ b核易位抑制剂的处理SN-50降低了Lef1的表达。通过生物信息学分析选择了小鼠和人之间保守的NF-κ b结合位点,并定位在Lef1转录起始位点上游的14 kb处。通过染色质免疫沉淀法证实NF-κ b与该位点的结合。软骨细胞中NF-κ b与Lef1/β-catenin的相互作用协同上调Lef1表达。我们的结果表明,NF-κ b在关节炎软骨细胞或软骨变性中Lef1表达中起关键作用。

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