The role of complement in trauma and fracture healing.

The complement system, as part of innate immunity, is activated immediately after trauma in response to various pathogen- and danger-associated molecular patterns (PAMPs and DAMPs), and helps to eliminate microorganisms and damaged cells. However, recent data indicate an extended role of complement far beyond pure "killing", which includes regulation of the cytokine/chemokine network, influencing physiological barriers, interaction with the coagulation cascade, and even involvement with bone metabolism and repair. Complement-induced hyper-activation and dysfunction reveal the dark side of this system, leading to complications such as sepsis, multiple-organ dysfunction, delayed fracture healing, and unfavorable outcome. Thus, the present review focuses on less known regulatory roles of the complement system after trauma and during fracture healing, rather than on its bacterial and cellular "killing functions". In particular, various complement crosstalks after trauma, including the coagulation cascade and apoptosis system, appear to be crucially involved early after trauma. Long-term effects of complement on tissue regeneration after fracture and bone turnover are also considered, providing new insights into innate immunity in local and systemic complement-driven effects after trauma.