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Scientific Articles   |    
Alterations in Recovery from Spinal Cord Injury in Rats Treated with Recombinant Human Bone Morphogenetic Protein-2 for Posterolateral Arthrodesis
Anton E. Dmitriev, PhD1; Suzanne Castner, BSc2; Ronald A. Lehman, Jr., MD3; Geoffrey S.F. Ling, MD, PhD2; Aviva J. Symes, PhD2
1 Spine Research Center, Walter Reed Army Medical Center, P.O. Box 59037, Washington, DC 20012. E-mail address: aedortho@gmail.com
2 Departments of Pharmacology (S.C. and A.J.S.) and Neurology (G.S.F.L.), Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814
3 The Integrated Department of Orthopaedics and Rehabilitation, Walter Reed Army Medical Center, 6900 Georgia Avenue N.W., Washington, DC 20307
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Disclosure: One or more of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of an aspect of this work. In addition, one or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.

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Investigation performed at the Uniformed Services University of the Health Sciences, Bethesda, Maryland

A commentary by S. Tim Yoon, MD, PhD, is linked to the online version of this article at jbjs.org.

Disclaimer: The views expressed in this manuscript are those of the authors and do not reflect the official policy of the Department of Army, Department of Defense, or the U.S. Government. Four of the authors are employees of the U.S. Government. This work was prepared as part of their official duties and, as such, there is no copyright to be transferred.


Copyright © 2011 by The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2011 Aug 17;93(16):1488-1499. doi: 10.2106/JBJS.J.00904
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Abstract

Background: 

Treatment of trauma-related spinal instability with use of recombinant human bone morphogenetic protein-2 (rhBMP-2) may appear as a viable option, but little is known of the direct effects of rhBMP-2 on the injured spinal cord. In the current study, we investigated the acute and long-term effects of using rhBMP-2 in the posterolateral spine at the level of a spinal cord injury in rats.

Methods: 

Fifty-two rats underwent a T10 dorsal hemisection and were assigned to one of two groups: the vehicle control group (twenty-four rats) or the rhBMP-2 group (twenty-four rats). Within each group, animals were further subdivided according to the follow-up period: one week and six weeks after the lesion. For the acute phase, an additional group of four rats received recombinant human albumin, to account for the cross-species inflammatory response. Postoperatively, locomotor function was assessed on a weekly basis with use of an open field scale and digital footprint analysis. After the animals were killed, they were perfused and the spinal cords analyzed for inflammatory markers, gliosis, and extracellular matrix proteins with use of immunohistochemistry.

Results: 

At one week, there was a significant increase in reactive astrocyte, macrophage-microglia, and fibroblast immunoreactivity around the lesion in the rhBMP-2-treated rats relative to controls. Additionally, there was increased staining for chondroitin sulfate proteoglycans. Similar intergroup morphologic differences persisted at six weeks. Functionally, in the acute phase, rhBMP-2-treated animals demonstrated more open field and fine motor control deficits relative to the controls. By six weeks, both groups had equivalent functional scores, but those treated with rhBMP-2 retained significantly greater paw angle changes than the control animals.

Conclusions: 

Our findings indicate that in a rat model, rhBMP-2 use in the vicinity of a penetrating spinal cord injury triggers detrimental changes in the morphology of the spinal cord lesion and alters functional recovery.

Clinical Relevance: 

Our findings suggest that rhBMP-2 used in its current form may impede neurologic recovery in a subset of patients with an open dural spinal cord injury, as we observed detrimental effects on histological and behavioral testing in our rat model.

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    Accreditation Statement
    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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