Anti-inflammatory treatment increases angiogenesis during early fracture healing

Abstract

Both inflammation and angiogenesis are crucial for normal fracture healing. The goal of this work was to determine how anti-inflammatory treatment affects angiogenesis during early stages of fracture repair. Tibia fractures were created in adult mice and animals were treated with indomethacin (2mg/kg/day), a non-steroidal anti-inflammatory drug, or PBS once a day beginning from 1 day before fracture and continuing to 6days after fracture. Animals were killed at 7, 14, and 28days after injury for histomorphometric analysis of fracture healing. A second group of animals were killed at 3 and 7days after injury to measure tissue levels of VEGF and interleukin-1 beta (IL-1β). A third group of animals were killed at 3 and 7days after injury for stereology analysis of macrophage and neutrophil infiltration and tissue vascularization. Indomethacin significantly decreased bone and cartilage formation at 7days after fracture compared to controls. Indomethacin decreased the tissue levels of IL-1β at 3days after fracture but did not affect the recruitment of macrophages or neutrophils to injured limbs. Indomethacin-treated fractures had similar length density and surface density of vasculature as the controls at 3days after injury. At 7days after fracture, vasculature in indomethacin-treated fractures exhibited higher length density and surface density than that in controls. By 28days after injury, indomethacin-treated fractures still exhibited defects in fracture repair. Anti-inflammatory treatments using indomethacin impair bone and cartilage formation and increase tissue vascularization in the callus during early fracture healing.