泛素连接酶在骨形成调节中的作用

Role of E3 ubiquitin ligase in the regulation of bone formation

泛素-蛋白酶体系统是维持细胞内蛋白质稳态和功能的重要调节途径,泛素化参与调节细胞的增生、分化和存活,泛素化调节异常可导致代谢性骨病、肿瘤等疾病的发生。越来越多的证据表明泛素-蛋白酶体系统参与调控成骨细胞功能和骨形成。泛素连接酶(E3 ubiquitin ligases,E3)作为泛素和底物蛋白之间的衔接分子可特异性识别底物,在骨形成相关蛋白调节和骨转换过程中具有重要的意义。既往研究表明E3连接酶通过介导酪氨酸激酶受体、信号蛋白和转录因子等参与成骨细胞增生、分化、存活和骨形成的调节。Smurf1、Cbl和SCFβ-Tr CP等E3连接酶可特异性介导Runx2、MEKK2、Jun B、β-catenin、Gli2、ATF4等成骨细胞分化重要调节蛋白的降解,抑制成骨功能。E3连接酶作为促进骨形成和减少骨丢失理想的治疗靶标,具有广阔的研究前景。本文对E3连接酶在骨形成调节中的作用及机制进行回顾和总结。

The ubiquitination-proteasome and degradation system is an essential process that regulates protein homeostasis and functions. This system is involved in the regulation of cell proliferation,differentiation and survival,and dysregulations in this system will lead to metabolic bone diseases and cancer. Increasing evidence shows that the ubiquitin-proteasome system was involved in the regulation of osteoblasts and bone formation. The ubiquitin-protein ligases（ E3）,which is the most abundant group of enzymes involved in ubiquitination,is thought to recognize substrate specifically in ubiquitination by serving as an adaptor between the ubiquitin-protein conjugation machinery and the target molecule. Because of their substrate specificity,E3 ubiquitin ligases are of major significance in controlling bone formation. Previous studies showed that the E3 ubiquitin ligase regulates bone formation by controlling the degradation of several receptor tyrosine kinases,signaling molecules and transcription factors in osteoblast which regulates osteoblast proliferation,differentiation and survival. For example,the E3 ligases,Smurf1,Cbl and SCFβ-Tr CP,could promote degradation of Runx2,MEKK2,Jun B,β-catenin,Gli2,ATF4 to inhibit their functions which were required for osteoblast differentiation. Targeting E3 ubiquitin ligases may be a potential therapeutic strategy to promote osteogenesis and to reduce osteoporosis. Here,we review the mechanisms of action of E3 ubiquitin ligases in the regulation of bone formation.