Modulation of Macrophage Activity During Fracture Repair Has Differential Effects in Young Adult and Elderly Mice

Objectives: Advanced age is a factor associated with altered fracture healing. Delays in healing may increase the incidence of complications in the elderly, who are less able to tolerate long periods of immobilization and activity restrictions. This study sought to determine whether fracture repair could be enhanced in elderly animals by: (1) inhibiting macrophage activation, (2) blocking the M-CSF receptor c-fms, and (3) inhibiting monocyte trafficking using CC chemokine receptor-2 (CCR2) knockout mice. Methods: Closed unstable tibial shaft fractures were produced in mice aged 4, 12, and 78 weeks. Mice were then fed a diet containing PLX3397 or a control diet from days 1-10 after injury. Fractures were similarly made in CCR2(-/-) mice aged 78 weeks. The fracture callus was collected during fracture healing and was assessed for its size and the presence of macrophages, both of which were evaluated using the Mann-Whitney U test. Results: PLX3397 treatment resulted in a decrease in the number of macrophages in the fracture callus at day 5. Calluses in juvenile mice trended toward being smaller compared with those in elderly mice (P = 0.08). There was also a trend toward larger callus size and increased bone formation in PLX3397-treated elderly animals when compared with those of the control animals (P = 0.12). Similar increases in bone formation (P = 0.013) and decreases in cartilage within the callus (P = 0.03) were seen at day 10 in CCR2(-/-) mice. Conclusions: The inhibition of macrophages in elderly mice may lead to an acceleration of fracture healing. Altering macrophage activation after fracture may represent a therapeutic strategy for preventing delayed healing and nonunion in the elderly.