Rejuvenating fracture repair: The role of the macrophage and Beta-catenin

 描述(申请人提供)：骨骼修复的速度随着年龄的增长而减慢，对这种延迟修复过程的机制知之甚少。愈合缓慢是导致老年人骨折时发病率甚至死亡率增加的原因。在骨折修复过程中，未分化的间充质细胞聚集并分化为成骨细胞，以重建骨的力学性能。我们发现，正常的骨折修复需要β-连环蛋白的精确调控，而上调和下调都会抑制细胞成为成骨细胞的能力。随着年龄的增长，骨折修复过程中β-连环蛋白水平显著增加，这与抑制未分化细胞成为成骨细胞有关。此外，我们还发现幼鼠的造血细胞可以抑制β-连环蛋白并使修复恢复活力。在这里，我们将使用异慢性异生实验，其中小鼠和老年鼠共享血液供应，以及骨髓移植实验，以确定负责返老还童效应的细胞类型。此外，我们将使用转基因小鼠研究年轻造血细胞产生的分泌因子在衰老过程中骨修复中的作用，这些因子是通过质谱学鉴定出来的。这项工作将确定新的潜在治疗方法，以改善老年骨折修复，最终降低与老年人受伤相关的发病率。

 DESCRIPTION (provided by applicant): The rate of bone repair slows with aging, and little is known about the mechanisms responsible for this delayed repair process. The slow healing is responsible for increased morbidity and even mortality when older adults sustain a fracture. During fracture repair, undifferentiated mesenchymal cells accumulate and differentiate to osteoblasts to reestablish the mechanical properties of bone. We discovered that β-catenin needs to be precisely regulated for normal fracture repair, and both up and down regulation inhibit the ability of cells to become osteoblasts. β-catenin protein level was substantially increased during fracture repair with aging, and this was associated with an inhibition of undifferentiated cells to become osteoblasts. Furthermore, we found that hematopoetic cells from young mice could suppress β-catenin and rejuvenate repair. Here we will use heterochronic parabiosis experiments, in which young and old mice share a blood supply, and bone marrow transplantation experiments to identify the cell type responsible for the rejuvenation effect. Furthermore, we will study the role of secreted factors produced by young hematopoetic cells, that we identified using mass spectroscopy, in bone repair in aging using genetically modified mice. This work will identify novel potential therapies to improve fracture repair in aging, ultimately reducing the morbidity associated with injury in older individuals.