Correction of Immune Response Improves Aged Fracture Healing

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ABSTRACT Bone fractures occur in 50% of the population causing significant morbidity and mortality and costing more than $20 billion in health care annually. Fracture repair is a complex process that involves numerous signaling molecules and cellular processes, all of which have not been fully identified. Factors, such as advanced age, can negatively affect this process thereby impairing recovery and proper bone healing. Our preliminary data indicate that macrophages recruited to the site of bone injury in young mice create a niche that leads to robust tissue repair. With age, the constituents of the secreted niche are lost resulting in diminished bone healing. Our previous parabiosis and bone marrow transplant models as well as in vitro cell culture studies have confirmed that the young macrophage niche is able to improve fracture repair and osteoblast differentiation in aged mice. Notable within these investigations, rejuvenation coincided with decreased numbers of classically activated, pro- inflammatory, M1 macrophages at the site of injury but increased alternatively activated, regenerative, M2 macrophages. To recapitulate these findings using a therapeutic approach, we treated a small cohort of aged mice with Maresin1 shortly after bone fracture injury. Relative to vehicle controls, treated mice displayed decreased, control inflammation after injury and the fracture calluses from these mice contained more mineral. Furthermore, media conditioned by macrophages treated with Maresin1 improved aged osteoblast differentiation, matrix production, and mineral formation. Within the proposed work here we will identify the mechanism by which Maresin1 treatment improves bone fracture healing and determine the constituents of the niche secreted by macrophages which improves aged osteoblast function.