Effects of Aging on Macrophages and Bone Regeneration

描述(申请人提供)：脆性骨折在我们的老龄化人口中继续导致显著的发病率和死亡率，特别是因为骨折愈合过程中的延迟愈合和不愈合在老年人中更为常见。骨折愈合的能力随着年龄的增长而下降，仍然需要有效的治疗来促进骨折的愈合。衰老还会导致免疫系统的显着变化，而衰老免疫细胞在骨再生障碍中的作用尚未得到研究。我们的建议将检验这一假说，即在老年人骨折修复过程中，髓系细胞的年龄相关变化促进功能障碍的骨再生。我们认为，虽然巨噬细胞有利于年轻小鼠的骨修复，但在老年小鼠中，巨噬细胞表型和功能的变化导致了巨噬细胞对骨再生的不利影响。我们的建议侧重于确定巨噬细胞随年龄的变化如何影响其在骨再生中与成骨细胞和间充质干细胞的功能相互作用。一个长期的目标是开发针对巨噬细胞的治疗方法，以促进老年患者的骨折修复。我们的具体目标是：1)确定衰老对骨巨噬细胞在促进成骨细胞分化和功能中的作用。2)通过幼年动物的骨髓移植，展示负责老年动物骨折愈合的细胞类型(S)。3)确定衰老对巨噬细胞和间充质干细胞(MSC)相互作用的影响，并确定巨噬细胞中对髓系细胞受体TREM2的需求：MSC相互作用

DESCRIPTION (provided by applicant): Fragility fractures continue to cause significant morbidity and mortality in our aging population particularly because delayed healing and non-union during fracture healing is more common in the elderly. The ability to heal fractures decreases with age and effective therapies to enhance fracture healing are still needed. Aging also leads to significant changes in the immune system and the role of aging immune cells in the impairment of bone regeneration has not been examined. Our proposal will examine the hypothesis that age-related changes in myeloid cells promote dysfunctional bone regeneration during fracture repair in the elderly. We propose that while macrophages are beneficial to bone repair in young mice, in aged mice, the changes in macrophage phenotype and function lead to a detrimental effect of macrophages on bone regeneration. Our proposal focuses on determining how changes in macrophages with aging affect their functional interactions with osteoblasts and mesenchymal stem cells in bone regeneration. A long-term goal is the development of therapeutics directed at macrophages that will enhance fracture repair in geriatric patients. Our specific aims are: 1) Determine the effect of aging on osteal macrophages in the promotion of osteoblast differentiation and function. 2) Demonstrate the cell type(s) responsible for the "rescue" of fracture healing in older animals by bone marrow transplant from young animals. 3) Determine the effect of aging on macrophage and mesenchymal stem cell (MSC) interactions and determine the requirement for the myeloid cell receptor TREM2 in macrophage: MSC interactions