Alterations in Recovery from Spinal Cord Injury in Rats Treated with Recombinant Human Bone Morphogenetic Protein-2 for Posterolateral Arthrodesis

• Published in: Journal of bone and joint surgery. American volume 2011-08, Vol.93 (16), p.1488-1499
• Main Authors: Dmitriev, Anton E, Castner, Suzanne, Lehman, Ronald A, Ling, Geoffrey S.F, Symes, Aviva J
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Bone Morphogenetic Protein 2 - therapeutic use; Cerebrospinal fluid. Meninges. Spinal cord; Chondroitin Sulfate Proteoglycans - metabolism; Diseases of the osteoarticular system; Female; Glial Fibrillary Acidic Protein - metabolism; Medical sciences; Motor Activity - drug effects; Nervous system (semeiology, syndromes); Neurology; Orthopedic surgery; Rats; Rats, Sprague-Dawley; Recovery of Function - drug effects; Spinal Cord - drug effects; Spinal Cord - metabolism; Spinal Cord Injuries - drug therapy; Spinal Cord Injuries - metabolism; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Treatment Outcome; Vimentin - metabolism
• ISSN: 0021-9355; 1535-1386
• DOI: 10.2106/JBJS.J.00904

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 groupsthe 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 periodone 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.