Metabolic Endotoxemia and Inhibition of Direct Bone Regeneration: A Pilot Study

Aims: Clinical and pre-clinical studies have demonstrated that alcohol abuse, aging, diabetes and rheumatoid arthritis are associated with increased risk of fractures compounded with impaired fracture repair. We note that these and other pathologies are characterized by chronic inflammation (CI) as a risk factor. How these CI pathologies inhibit bone repair is unclear, but one candidate mediator is endotoxin (lipopolysaccharide/LPS). LPS promotes inflammation and is present in increased serum concentrations in some inflammatory conditions. The distraction osteogenesis (DO) model developed in this laboratory provides the opportunity to isolate and study the effects of CI on direct bone formation during bone regeneration. The aim of this study was to determine whether endotoxin at concentrations that mimic levels reported in chronic inflammatory conditions would impair bone formation in a mouse model of DO. Study Design: Mouse bone repair study. Place and Duration of Study: Arkansas Children's Hospital Research Institute, Little Rock, Arkansas, April to June 2009. Methodology: LPS or vehicle (PBS) was chronically administered to 11-week old mice via alzet pump. Mice underwent the DO protocol concurrently with LPS administration. Radiographic and histologic quantitation was performed on the DO gap to determine the amount of new bone formed. Results: Radiographic (51.9 ± 7% vehicle vs 21.0 ± 7.3% LPS: P < .01) and histologic (68.1 ± 8.5% vehicle vs 33.6 ±10.3% LPS; P < .02) results indicate that bone formation during DO was significantly decreased in LPS treated versus vehicle treated mice. Conclusion: The magnitude of the osteoinhibitory effects of systemic LPS in this mouse model of CI was equivalent to two months of ethanol treatment, 24 months of aging, or two months of Type 1 diabetes. These results support the hypothesis that LPS exposure could be responsible for the decreased bone formation observed in chronic inflammatory conditions