Dual Role of 5-Lipoxygenase in Osteoclastogenesis in Bacterial-induced Apical Periodontitis

• 5-lipoxygenase presents a functional role in apical periodontitis development through the regulation of canonic receptor activator of nuclear factor kappa-B–receptor activator of nuclear factor kappa-B ligand–osteoprotegerin osteoclastogenesis signaling.
• Early on, osteoclastogenesis signaling is down-regulated by the inhibition of 5-LO, but long-term inhibition fails to prevent expression of bone catabolic mediators.
• Ultimately, inhibition of 5-lipoxygenase did not prevent osteoclast formation and periapical bone resorption probably because of detrimental regulation of cytokines, chemokines, and osteopontin in early versus late apical periodontitis course.

IntroductionThe aim of this study was to evaluate the role of 5-lipoxigenase (5-LO) in the signaling for osteoclast formation and bone resorption in apical periodontitis (AP) after root canal contamination with oral bacteria.MethodsAP was experimentally induced in C57BL/6 mice because of contamination of the root canals left open to the oral environment. MK886 was used as a systemic inhibitor of 5-LO (5 mg/kg, daily). After 7, 14, 21, and 28 days, the animals were euthanized, and tissues were removed for gene evaluation by quantitative reverse transcriptase polymerase chain reaction, histologic analysis, and tartrate-resistant acid phosphatase staining.ResultsRoot canal contamination induced the expression of messenger RNA for 5-LO and leukotriene B4 receptors BLT1 and BLT2. The administration of the 5-LO inhibitor reduced early receptor activator of nuclear factor kappa-B and receptor activator of nuclear factor kappa-B ligand synthesis but augmented late receptor activator of nuclear factor kappa-B ligand and osteoprotegerin expression during the course of AP development. Interestingly, long-term inhibition of 5-LO resulted in increased bone resorption and induced tartrate-resistant acid phosphatase–positive osteoclast formation. The divergent findings related to 5-LO inhibition in osteoclastogenesis signaling, osteoclast formation, and bone resorption were accompanied by differently regulated inflammatory gene expression. Il1b, Il11, Ccl3, Ccl7, and Spp were down-regulated by the 5-LO inhibitor in early AP, but later on Il11, Ccl3, Cxcl9, Cxcl15, and Spp were up-regulated.Conclusions5-LO presented a dual role in osteoclastogenesis during the course of AP development. Early on, osteoclastogenesis signaling was down-regulated by the inhibition of 5-LO, but long-term inhibition failed to prevent synthesis of catabolic mediators that resulted in increased bone loss.