Defective bone repair in diclofenac treated C57Bl6 mice with and without lipopolysaccharide induced systemic inflammation

• Published in: Journal of cellular physiology 2019-03, Vol.234 (3), p.3078-3087
• Main Authors: Ramirez‐Garcia‐Luna, Jose L., Wong, Timothy H., Chan, Daniel, Al‐Saran, Yazeed, Awlia, Ayman, Abou‐Rjeili, Mira, Ouellet, Suzie, Akoury, Elie, Lemarié, Catherine A., Henderson, Janet E., Martineau, Paul A.
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Biocompatibility; Biomedical materials; Bone growth; Bone healing; Computed tomography; Diclofenac; Diclofenac - pharmacology; Endothelial cells; Endothelial Cells - drug effects; Femur; fracture; Healing; Hemostasis; Hemostatics; Humans; Inflammation; Inflammation - chemically induced; Inflammation - drug therapy; Inflammation - pathology; Inflammatory response; Lipopolysaccharides; lipopolysaccharides (LPS)‐induced inflammation; Lipopolysaccharides - toxicity; Macrophages; Macrophages - drug effects; Male; Mast cells; Mice; Nonsteroidal anti-inflammatory drugs; nonsteroidal anti‐inflammatory drugs (NSAID); Orthopedic Procedures - adverse effects; Osteoblasts - drug effects; Osteoclasts - drug effects; Pain; Pain - diagnostic imaging; Pain - drug therapy; Pain - pathology; Regeneration; Regeneration (physiology); Repair; Rodents; Surgery; Trauma; Wounds and Injuries - complications; Wounds and Injuries - diagnostic imaging; Wounds and Injuries - drug therapy; Wounds and Injuries - pathology; X-Ray Microtomography
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.27128

Bone repair after trauma or surgical intervention involves a tightly regulated cascade of events that starts with hemostasis and an inflammatory response, which are critical for successful healing. Nonsteroidal anti‐inflammatory drugs (NSAID) are routinely prescribed for pain relief despite their potential inhibitory effect on bone repair. The goal of this study was to determine the impact of administration of the non‐selective NSAID diclofenac in the inflammatory phase of bone repair in mice with or without lipopolysaccharide‐induced systemic inflammation. Repair of femoral window defects was characterized using micro computed tomography imaging and histological analyses at 2 weeks postoperative. The data indicate (a) impaired bone regeneration associated with reduced osteoblast, osteoclast, and macrophage activity; (b) changes in the number, activity, and distribution of mast cells in regenerating bone; and (c) impaired angiogenesis due to a direct toxic effect of diclofenac on vascular endothelial cells. The results of this study provide strong evidence to support the conjecture that administration of NSAIDs in the first 2 weeks after orthopaedic surgery disrupts the healing cascade and exacerbates the negative effects of systemic inflammation on the repair process. Bone repair in mice chronically treated with diclofenac, a nonselective nonsteroidal anti‐inflammatory drug (NSAID), with or without lipopolysaccharides‐induced systemic inflammation was found to be disrupted due to inhibitory effects on osteoblasts, osteoclasts, macrophages, and mast cells, as well as by a direct toxic effect on vascular endothelial cells. The results of this study provide strong evidence to support the conjecture that administration of NSAIDs in the first 2 weeks after orthopaedic surgery disrupts the healing cascade and also appears to exacerbate the negative effects of systemic inflammation on the repair process.