Wnt信号通路对软骨和软骨下骨双靶向调控及其在骨关节炎进展中的作用

The role of Wnt signaling pathway in osteoarthritis via the dual-targeted regulation of cartilage and subchondral bone

目的综述Wnt信号通路在骨关节炎(osteoarthritis,OA)发生发展中的活性变化,及其对软骨、软骨下骨的双靶向调控和两者间信息交流对OA进程的影响和机制。方法查阅近年在体内外实验研究及临床研究中,OA和非OA状态下Wnt信号通路对关节软骨、软骨下骨调控作用及软骨与软骨下骨间信息交流的相关文献,并对其作用机制进行分析总结。结果 Wnt信号可通过依赖β-catenin的经典或不依赖β-catenin的非经典Wnt信号通路及其与其他信号通路的交联,调控软骨细胞、成骨细胞的分化和功能,进而影响软骨及骨的代谢。过度激活Wnt信号可加重软骨OA样退变,并且Wnt信号通路可激活下游蛋白Wnt1诱导的信号通路蛋白1调控OA进展,还可通过软骨及软骨下骨中不同细胞间建立的缝隙连接,直接进行分子交流调控OA的发生发展。关节腔内注射Wnt信号通路抑制剂SM04690可以抑制OA进程;在成骨细胞中过表达Wnt信号通路抑制剂Dickkopf可以拮抗VEGF对软骨细胞的作用,并抑制其基质的分解代谢。结论 Wnt信号通路及其与其他信号分子的交互作用,可调控软骨和软骨下骨的代谢和功能及两者间信息交流,因此在OA的发生发展中发挥重要作用,有望成为OA治疗的新靶点。

Objective To summarize the active changes of Wnt signaling pathway in osteoarthritis(OA)as well as the influence and mechanism of dual-targeted regulation on cartilage and subchondral bone and the role of crosstalk between them on OA process.Methods The relevant literature concerning the articular cartilage,subchondral bone,and crosstalk between them in OA and non-OA states by Wnt signaling pathway in vivo and vitro experimental studies and clinical studies in recent years was reviewed,and the mechanism was analyzed and summarized.Results Wnt signaling can regulate the differentiation and function of chondrocytes and osteoblasts through the classicβ-catenin-dependent or non-classicalβ-catenin-independent Wnt signaling pathway and its cross-linking with other signaling pathways,thereby affecting the cartilage and bone metabolism.Moreover,Wnt signaling pathway can activate the downstream protein Wnt1-inducible-signaling pathway protein 1 to regulate the progress of OA and it also can be established gap junctions between different cells in cartilage and subchondral bone to communicate molecules directly to regulate OA occurrence and development.Intra-articular injection of Wnt signaling inhibitor SM04690 can inhibit the progress of OA,and overexpression of Wnt signaling pathway inhibitor Dickkopf in osteoblasts can antagonize the role of vascular endothelial growth factor work on chondrocytes and inhibit the catabolism of its matrix.Conclusion The regulation of metabolism and function of cartilage and subchondral bone and crosstalk between them is through interactions among Wnt signaling pathway and molecules of other signaling.Therefore,it plays an vital role in the occurrence and development of OA and is expected to become a new target of OA treatment through intervention and regulation of Wnt signaling pathway.