糖基转移酶在骨关节炎中的表达及IGF-1/AKT/AP-1通路介导调控的机制

The imbalance of proteoglycan synthesis and degradation is the salient features of osteoarthritis (OA). The glycosyltransferases (GTs) catalyze the proteoglycan by the stepwise addition of each sugar residue, and the abnormality of GTs may lead to a progressive deterioration of OA. Our previous studies indicated that Angelica Sinensis Polysaccharides can improve PGs synthesis of chondrocytes on rat OA model in vivo and in vitro, which is due to the promotion of the gene expression of GTs and may be mediated by IGF-1 signaling pathway. IGF-1R inhibitors can inhibit the mRNA expression of GTs. Therefore, we put forward the research hypothesis that IGF-1 dominates the expression and regulation of GTs by the IGF-1R/AKT/AP-1 signaling pathway in chondrocyte. Our goals for this project are to prove that the expression of GTs in the cartilage of OA patients is lower than those in the cartilage of non-OA patients, and further to clarify that the regulatory mechanisms of GTs is mediated by the IGF-1R/AKT/AP-1 signaling pathway both in vivo and in vitro. This project will allow us to fully understand the important role of GTs in the process of OA and its expression regulation mechanism. Meanwhile, it will provide new targets for exploring the treatment of OA. The academic thinking and research of this project has not been reported at home and abroad.

蛋白多糖合成和降解的失衡是骨关节炎（OA）的显著特征，糖基转移酶（GTs）主要催化蛋白多糖的合成，它的异常可能导致OA的进行性加重。本室前期发现，当归多糖上调软骨细胞GTs基因表达可能是经IGF-1信号介导的，IGF-1R抑制剂能明显抑制GTs的基因表达（见工作基础）。综合文献可以推测： IGF-1通过IGF-1R/AKT/AP-1信号通路主导了软骨细胞GTs的表达调控。本项目拟先证实GTs在OA患者软骨中低表达，再利用细胞实验证实IGF-1/IGF-1R/AKT/AP-1信号通路主导了软骨细胞GTs的转录调控，同时在整体动物水平证实IGF-1主要通过AKT/AP-1信号通路上调软骨细胞GTs表达，促进基质蛋白多糖合成，缓解OA病变，这将使我们充分认识GTs在OA进程中的重要地位及其表达调控机制，为认识OA的发生发展机制和探索其治疗提供新的靶点。本项目的学术思想及研究内容国内外尚未见报道。

蛋白多糖合成和降解的失衡是骨关节炎（OA）的显著特征，糖基转移酶（GTs）主要催化蛋白多糖的合成，它的异常可能导致OA的进行性加重。本项目在临床标本水平证实OA患者关节软骨组织中GTs的蛋白表达和GAG含量明显低于正常关节软骨组织。相较于人正常关节软骨细胞，OA关节软骨细胞中IGF-1R/AKT/AP-1通路活化状态、GTs基因表达及GAG合成均降低。进一步利用工具药及质粒在细胞水平证实IGF-1/IGF-1R/AKT/AP-1信号通路主导了软骨细胞GTs的表达调控。整体动物水平发现孕期地塞米松暴露导致子代大鼠关节软骨发育不良及OA易感性增加的原因也是由于GC-IGF1/AKT/AP-1轴的低基础活性，GTs低表达所致。本研究结果为我们全面认识GTs在OA进程中的重要地位及其表达调控机制，更好的理解OA的发生发展机制，同时也为后续进一步研究和防治OA提供了有效的理论依据。