Pharmacological inhibition of 5-lipoxygenase accelerates and enhances fracture-healing

Background: Loss of cyclooxygenase-2 activity is known to impair fracture-healing in animal models and to inhibit heterotopic ossification in humans. Cyclooxygenase-2 is the rate-limiting enzyme involved in the conversion of arachidonic acid into prostaglandins. Arachidonic acid also is a substrate for 5-lipoxygenase, which catalyzes the initial steps in leukotriene synthesis. In contrast to cyclooxygenase-2, genetic ablation of 5-lipoxygenase accelerates and enhances fracture-healing in mice. The goal of this study was to determine if systemic inhibition of 5-lipoxygenase with an orally delivered drug could accelerate fracture-healing. Methods: Closed femoral fractures were made in Sprague-Dawley rats. The rats were treated with oral doses of vehicle (ninety-five rats), celecoxib (fifty-nine rats), or AA-861 (a 5-lipoxygenase inhibitor; eighty-nine rats). Fracture-healing was measured with use of radiographs, histomorphometry, and biomechanical testing. Effects of drug treatments on callus cell proliferation and gene expression were determined by incorporation of bromodeoxyuridine and quantitative polymerase chain reactions, respectively. Results: AA-861 treatment decreased fracture-bridging time, significantly increased early callus cartilage (5.6-fold; p < 0.001) and bone formation (4.2-fold; p = 0.015), and significantly increased callus mechanical properties compared with the vehicle-treated rat fractures. Callus cell proliferation rate was increased by AA-861 treatment, compared with vehicle, at day 2 after fracture (3.68 % compared with 2.08%; p < 0.001; 95 % confidence interval, 22.81 to 20.039