In contrast to most vertebrate tissues, which heal by forming scar tissue, bone heals through regeneration. Fracture repair is a highly complex and coordinated process involving the interaction of many cell types. It occurs in three distinct but overlapping stages: the early inflammatory stage, in which inflammatory cells, including neutrophils and macrophages, infiltrate and debride the injury; the regenerative stage; and the later remodeling stage. The initial inflammatory stage appears to be crucial for successful healing, perhaps because the chemical signals released initiate a cascade of events culminating in skeletal repair. Understanding the role of inflammation during bone fracture healing may lead to the development of new methods to optimize the healing of traumatic skeletal injuries.
The authors examine fracture healing in mice lacking the chemokine receptor Ccr2. Signaling through Ccr2 regulates osteoclast function, and is also responsible for trafficking cells of the monocyte lineage, including macrophages, to sites of injury. In normal mice, the expression of Ccr2 and its ligand Ccl2 are high after fracture. In the absence of Ccr2, acute infiltration of the fracture site by macrophages is significantly impaired, but recruitment of other cell types, such as neutrophils, is not affected. The reduction in macrophages is accompanied by reduced vascularity, impaired formation of skeletal tissues, and delayed bone remodeling owing to the decreased ability of Ccr2-negative osteoclasts to resorb bone tissue.
Implications and future directions
This study indicates that inflammatory cells, especially macrophages, play important roles in multiple steps during skeletal repair. Impaired macrophage function in human skeletal trauma patients could lead to delays in healing through a variety of mechanisms, including effects on the vascular system, stem cell differentiation and remodeling of the newly formed skeletal tissues. Future work will focus on identifying the molecular mechanisms that mediate macrophage function at the fracture site, and on treatment strategies to enhance the repair process in patients with skeletal injuries.