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. Fractures in the elderly are a significant cause of morbidity with a greater incidence of delayed and non-union healing compared with younger individuals. Insufficient bone formation that occurs with age remains incompletely understood. Aging also leads to significant changes in immune cells and the effects of immune cell aging on bone regeneration have not been directly explored. Our proposal focuses on determining how changes in macrophages with aging affect functional interactions with osteoblasts and mesenchymal stem cells in bone regeneration with the long-term goal of developing therapeutics directed at macrophages to enhance fracture repair in geriatric patients.