Wnt和Notch通路在老龄个体骨髓间充质干细胞成骨中的调控

Regulation of Wnt and Notch signaling pathways in the osteogenic differentiation of bone marrow-derived mesenchymal stem cells from aged individuals

社会老龄化的加剧使老年个体骨损伤修复问题愈发突出,骨髓间充质干细胞(BMSC)是一种与骨代谢再生密切相关的骨髓细胞,其生物学特性(形态、表面特征、细胞周期、端粒酶以及细胞内活性氧簇水平等)以及增殖分化能力在生物体年龄影响下均发生了改变,成骨能力下降,影响了骨损伤的修复速度和质量。探索其中分子机制对改善老龄个体骨损伤康复有至关重要作用。参与调控的信号中,Wnt和Notch近年日益受到关注,二者对老龄BMSC成骨的调控有交互作用。老龄机体的氧化应激反应增加而生长因子生成减少,Wnt通路的转录因子β-catenin与叉头家族转录因子的亲和力增加,不再与T细胞因子和淋巴增强因子结合,故BMSC成骨减弱。同时老龄个体骨髓中BMSC数量减少,Notch抑制BMSC成骨来维持祖细胞池中BMSC的数量。Wnt和Notch之间还存在相互作用,如Notch过表达能够削弱Wnt的影响等。此外,BMP-Smad转录因子活性下降,Hedgehog信号通路下调,亦影响着BMSC的成骨分化。本文对老龄个体BMSC生物学性能变化及其成骨分化过程中信号通路的调控作用进行综述,为老龄个体骨相关性疾病的治疗提供新思路。

The impaired bone healing process in aged individuals is a common clinical problem. Bone marrow-derived mesenchymal stem cells（BMSCs）, a group ofpluripotent stem cells located in the bone marrow, are functional cells of new bone formation and bone metabolism. Its biological characteristics（including cell morphology, surface features, cell cycle, and level of reactive oxygen species） and proliferation and differentiation ability are varied with age, which directly affects the bone healing speed and quality at the bone injury site. Signaling pathways play a crucial role in the osteogenic differentiation of BMSCs from aged individuals. Wnt and Notch signaling pathways have been widely reported and have attracted increasing attention from the scholars in recent years. The changes of oxidative stress and growth factors among aged individuals inhibit β-catenin activity directly by preventing β-catenin and binding its target site T cell factor and lymph enhancement factor instead of the binding fork head transcription factor and repress target gene expressions. Notch signaling pathway represses the differentiation and promotes the proliferation of BMSCs to maintain the number of BMSCs in bone marrow. The cross talk is between Notch and Wnt/ β-catenin signaling pathways. Notch1 overexpression inhibits osteoblastogenesis by suppressing Wnt/β-catenin It also plays an important role in the osteogenic differentiation of BMSCs from aged individuals. Moreover, the reactive oxygen species（ROS） level down-regulates bone morpho-genetic protein（BMP）-Smads and Hedgehog. Several other pathways also participate in the regulation process. This review summarizes the mechanism that Wnt/β-catenin and Notch signaling pathways regulate the osteogenic differentiation of BMSCs from aged individuals. This review may provide a new approach for the treatment of bone-related diseases in the senior population.