Anti-inflammatory treatment increases angiogenesis during early fracture healing

• Published in: Archives of orthopaedic and trauma surgery Vol. 132; no. 8; pp. 1205 - 1213
• Main Authors: Lu, Chuanyong, Xing, Zhiqing, Wang, Xiaodong, Mao, Jeremy, Marcucio, Ralph S., Miclau, Theodore
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.08.2012; Springer Nature B.V
• Subjects: Angiogenesis; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Basic Science; Fracture Healing - drug effects; Fractures; Indomethacin - pharmacology; Indomethacin - therapeutic use; Male; Medicine; Medicine & Public Health; Mice; Neovascularization, Physiologic - drug effects; Orthopedics; Rodents; Angiogenesis; Inflammation; Indomethacin; Fracture repair; NSAID
• ISSN: 0936-8051; 1434-3916
• DOI: 10.1007/s00402-012-1525-4

Objectives 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. Methods Tibia fractures were created in adult mice and animals were treated with indomethacin (2 mg/kg/day), a non-steroidal anti-inflammatory drug, or PBS once a day beginning from 1 day before fracture and continuing to 6 days after fracture. Animals were killed at 7, 14, and 28 days after injury for histomorphometric analysis of fracture healing. A second group of animals were killed at 3 and 7 days after injury to measure tissue levels of VEGF and interleukin-1 beta (IL-1β). A third group of animals were killed at 3 and 7 days after injury for stereology analysis of macrophage and neutrophil infiltration and tissue vascularization. Results Indomethacin significantly decreased bone and cartilage formation at 7 days after fracture compared to controls. Indomethacin decreased the tissue levels of IL-1β at 3 days 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 3 days after injury. At 7 days after fracture, vasculature in indomethacin-treated fractures exhibited higher length density and surface density than that in controls. By 28 days after injury, indomethacin-treated fractures still exhibited defects in fracture repair. Conclusions Anti-inflammatory treatments using indomethacin impair bone and cartilage formation and increase tissue vascularization in the callus during early fracture healing.