The Role of Macrophages in Bone Development, Repair, and Aging

With age, the risk of sustaining a fracture increases, yet bone repair becomes a slower and more fibrotic process. This fracture healing process recapitulates the process of bone development, except that fracture repair is initiated with an inflammatory response to injury resulting in the recruitment of various immune cells, including macrophages. Interestingly, macrophages are present during early bone development, yet their function during this process is not well understood. Hence, the purpose of this study was to determine the functions of macrophages during bone development, repair and aging. Using transgenic mice to constitutively ablate macrophages, we demonstrated that macrophage deficiency impaired bone marrow progenitor cell differentiation resulting in decreased bone mineral density. Constitutive or temporal depletion of macrophages during fracture repair led to decreased callus formation and bone deposition resulting in impaired bone union. When we compared fracture healing between young and old mice, we found that old animals developed a slower and more fibrotic response to healing. To determine whether the age-related delays in fracture repair are associated with changes in this macrophage population with age, we performed parabiosis and cell transplantation experiments. We found that young macrophages rejuvenated fracture repair in older animals by suppressing fibrosis and promoting bone mineralization. Furthermore, conditioned media from young, but not old, macrophages rescued osteoblast differentiation of old bone marrow progenitor cells, and analysis of these cells indicated that old cells polarized towards a pro-inflammatory phenotype. Mass spectrometry analysis of young and old macrophage secretomes identified 56 â youth factorsâ . One of these factors, LRP1, was found to promote osteoblast differentiation of old progenitor cells. Taken together, these findings demonstrate a functional role for macrophages in bone formation and fracture repair, and that substitution of old macrophages with young macrophages rejuvenates fracture healing in older mice.Ph.D.2018-11-30 00:00:0