Investigation on the role of FGF-1 in CCN2 gene regulation and osteoarthritis

FGF-1强烈抑制CCN 2的基因表达，CCN 2使软骨再生，而FGF-1增强其自身在软骨细胞中的基因表达。这种作用被认为在FGF-1介导的骨关节炎发展中至关重要。为了找出介导这种基因调控的细胞内因子，我首先分析了从ENCODE数据库下载的染色质免疫沉淀（ChIP）测序数据。根据ChIP数据，CCN 2和FGF-1基因在近端启动子区均含有2个伴随H3 K4 me 2的区域，H3 K4 me 2是启动子、增强子和沉默子的标志。有趣的是，我发现了一个转录因子，它与两个基因的这两个区域之一结合。该转录因子的基因表达在人软骨细胞中得到证实。在通过siRNA沉默这些细胞中该因子的表达后，我评估了FGF-1对CCN 2和FGF-1基因的影响。 正如预期的那样，FGF-1在转录因子基因沉默后未能调节CCN 2和FGF-1基因。这些结果表明，这种单一的转录因子介导CCN 2阻遏和FGF-1的自诱导。本文提出了抑制该转录因子功能的分子在骨关节炎治疗中的用途。

FGF-1 strongly inhibits the gene expression of CCN2, which regenerates cartilage, whereas it enhances its own gene expression in chondrocytes. This effect is thought to be critical in osteoarthritis development mediated by FGF-1. In order to find out an intracellular factor that mediate this gene regulation, I initially analyzed chromatin immunoprecipitation (ChIP) sequencing data downloaded from the ENCODE database. According to the ChIP data, both CCN2 and FGF-1 genes contains 2 regions accompanied by H3K4me2, which is a hallmark of promoter, enhancer and silencer, in the proximal promoter area. Interestingly, I found a transcription factor that binds to one of these 2 regions of both genes. Gene expression of this transcription factor was confirmed in human chondrocytic cells. After silencing the expression of this factor in those cells by siRNAs, I evaluated the effect of FGF-1 on the CCN2 and FGF-1 genes. As expected, FGF-1 failed to regulate the CCN2 and FGF-1 genes after the silencing of the transcription factor gene. These results indicate that this single transcription factor mediates both CCN2 repression and auto-induction by FGF-1. Utility of a molecule that inhibits the function of this transcription factor in osteoarthritis treatment is suggested herein.