Wnt信号通路拮抗剂Dkk1调节骨代谢的最新进展

Progress in Dickkopf-1-mediated bone metabolism

背景:Dickkopf-1(Dkk1)是一种Wnt信号通路的可溶性胞外抑制剂,可以通过竞争性地结合Wnt蛋白的共同受体低密度脂蛋白受体相关蛋白5/6来阻断经典Wnt/β-catenin途径,进而调控Wnt/β-catenin途径下游靶基因的转录。目的:将Dkk1调节骨代谢的最新进展作一综述,为骨疾病的抗Dkk1治疗提供理论基础。方法:电子检索CBM和Medline数据库中1995至2012年关于Dkk1对骨代谢调节作用的文章,检索词为"Dkk1;骨重塑;骨疾病"和"Dkk1;bone remodeling;bone diseases"。纳入关于Dkk1调节骨代谢的高质量文献,排除重复发表文献。结果与结论:初始检索118篇文献,按纳入排除标准筛选后,选出36篇文献进行综述。骨组织时刻处于动态的重塑过程中,成骨细胞和破骨细胞的相互作用决定着骨形成和骨吸收之间的平衡。Dkk1可阻断Wnt/β-catenin信号通路、抑制骨形成,同时又通过与骨保护素/核因子ΚB受体活化因子配体/前体细胞表面受体轴的串话作用促进破骨细胞的分化与成熟。促进骨形成、抑制骨吸收是抗Dkk1治疗骨代谢相关疾病引起骨质缺失的主要机制与思路,且临床试验结果良好,Dkk1是一个非常有潜力的骨代谢疾病治疗靶点。

BACKGROUND： Dickkopf-1 is a soluble inhibitor of canonical Wnt/β-catenin signaling pathway. It blocks Wnt/β-catenin signaling by competitively binding with Wnt protein co-receptor LRP5/6 and then mediates downstream target gene transcription.OBJECTIVE： To review the research progress of Dickkopf-1-mediated bone metabolism, and to provide theoretical foundation of anti-Dickkopf-1 therapy for bone disease.METHODS： A computer-based online search was conducted in Medline and CBM databases from 1995-2012. Articles focusing on Dickkopf-1-mediated bone metabolism were collected using the keywords of “Dkk1; bone remodeling; bone diseases” in English and Chinese, respectively. High-quality studies were included, while repetitive studies were excluded.RESULTS AND CONCLUSION： 118 articles were obtained initially, and after screening procedure 36 literatures were selectively included in this review finally. Bone tissue is always in dynamic remodeling process. The interaction between osteoblasts and osteoclasts determines the dynamic balance between bone formation and bone resorption. Dickkopf-1 not only inhibits bone formation by blocking Wnt/β-catenin pathway, but also promotes osteoclast differentiation and maturation through the crosstalk with osteoprotegerin/receptor activator of nuclear factor-kappa B ligand/receptor activator of nuclear factor-kappa B axis. Promoting bone formation and inhibiting bone resorption is the biological mechanism of anti- Dickkopf-1 for preventing bone loss which occurs in bone metabolic diseases, and the clinical results are favorable. Therefore, Dickkopf-1 should be a potential target in the treatment of bone disease.