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Pharmacological Inhibition of 5-Lipoxygenase Accelerates and Enhances Fracture-Healing
Jessica A. Cottrell, PhD1; J. Patrick O'Connor, PhD1
1 Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, MSB E-659/Biochem, 185 South Orange Avenue, Newark, NJ 07103. E-mail address for J.P. O'Connor: oconnojp@umdnj.edu
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Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from the New Jersey Commission on Science and Technology. In addition, one or more of the authors or a member of his or her immediate family received, in any one year, payments or other benefits of less than $10,000 or a commitment or agreement to provide such benefits from commercial entities (Accelalox, Inc. and Celgene, Inc.).
Investigation performed at the Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, and Graduate School of Biomedical Sciences, Newark, New Jersey

The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2009 Nov 01;91(11):2653-2665. doi: 10.2106/JBJS.H.01844
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Abstract

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, -2.81 to -0.039) but was reduced by celecoxib treatment at day 4 after fracture (4.22% compared with 1.84%; p < 0.001; 95% confidence interval, 2.27 to 4.07). At day 10 after fracture, AA-861 and celecoxib treatment increased Type-II collagen mRNA levels (16.0-fold and 6.1-fold, respectively; p < 0.001 for both), but only AA-861 treatment caused an increase in Type-X collagen mRNA (6.3-fold; p < 0.001). AA-861 treatment significantly increased cyclooxygenase-2 (4.0-fold at day 10; p < 0.001) and osteopontin mRNA levels (3.6-fold at day 7; p = 0.024), while decreasing 5-lipoxygenase mRNA levels (5.6-fold at day 4; p < 0.001).

Conclusions: Systemic inhibition of 5-lipoxygenase with an orally delivered drug significantly accelerated and enhanced fracture-healing in this rat model. Gene expression analysis indicates that cyclooxygenase-2 is necessary for callus chondrocytes to progress into hypertrophy so as to complete endochondral ossification. Conversely, inhibition of 5-lipoxygenase alters the inflammatory response, which enhances callus chondrocyte hypertrophy and accelerates endochondral ossification.

Clinical Relevance: These results suggest a novel approach to the treatment of human fractures and demonstrate that arachidonic acid metabolism can be manipulated to inhibit or accelerate fracture-healing, underscoring the importance of this pathway in bone regeneration.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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