Discussion of the pathophysiology of acute spinal cord injury often refers to primary and secondary events. Primary spinal cord injury refers to the initial mechanical insult to the neuroparenchyma and can be subclassified into compression, contusion, laceration, and distraction.1 Secondary injury is the biochemical cascade that follows the primary injury and consists of vascular dysregulation, neurogenic shock, oxidative stress, immunologic injury, and excitotoxicity.1,2
Matrix metalloproteinases are zinc-dependent endopeptidases involved in the degradation of the extracellular matrix.3 Matrix metalloproteinases have a physiologic role in wound healing, angiogenesis, and embryologic development via their participation in extracellular matrix turnover. They are also involved in neuropathologic processes as diverse as tumor migration, axonal degeneration, lumbar disk herniation, multiple sclerosis, and acute spinal cord injury.4-10 Understanding of the role of MMPs in acute spinal cord injury is rapidly evolving. Recent research with mouse and rat spinal cord injury models suggests that MMP9, a gelatinase expressed by leukocytes and endothelial cells, is induced within 24 hours of primary spinal cord injury.8,11-13
Expression of MMP-9 has been associated with processes involved in early secondary injury, such as blood-spinal cord barrier permeability and neutrophil migration.8,12 Results obtained with a mouse open spinal cord injury model suggest that inhibition of MMP-9 expression improves locomotor outcome and reduces blood-spinal cord barrier disruption.8
Intervertebral disk disease is a frequent problem in dogs, accounts for approximately 2% of all diagnoses of canine disease, and represents the most common cause of acute spinal cord injury in this species.14,15 Intervertebral disk disease occurs most often (66% to 86% of cases) in the thoracolumbar vertebrae in dogs.16-18 Acute thoracolumbar IVDD may lead to sudden functional impairment of the spinal cord, ascending myelomalacia, and, ultimately, shortened duration and quality of life.19-22
Characterizing MMP activity in the CSF and blood of dogs with acute thoracolumbar IVDD is an important step in defining the pathophysiologic features of secondary spinal cord injury attributable to IVDD. It was our hypothesis, based on results from rodent spinal cord injury studies, that dogs with acute thoracolumbar IVDD would express MMP-9 in the CSF and have increased MMP-9 activity in the blood, compared with controls. It was also anticipated that dogs with MMP-9 activity would have a shorter history of neurologic dysfunction, be more severely affected, and require longer hospitalization stays than injured individuals without MMP-9 activity.
The purpose of the study reported here was to detect MMP-9 in serum and CSF and determine relationships between MMP activity, severity of disease, duration of clinical signs, and duration of hospitalization in dogs with acute IVDD.
Intervertebral disk disease
Abbott Laboratories, North Chicago, Ill.
Baxter Healthcare Corp, Deerfield, Ill.
BCA protein assay kit, Pierce, Rockford, Ill.
Invitrogen, Carlsbad, Calif.
Chemicon, Temecula, Calif.
AlphaImager, Alpha Innotech Corp, San Leandro, Calif.
Bionumerics, version 3.0, Applied Maths, Austin, Tex.
GraphPad Prism, version 4.0, GraphPad Software, San Diego, Calif.
Dumont RJ, Okonkwo DO, Verma S, et al.Acute spinal cord injury, part I: pathophysiologic mechanisms. Clin Neuropharmacol 2001; 24: 254–264.
Chandler S, Coates R, Gearing A, et al.Matrix metalloproteinases degrade myelin basic protein. Neurosci Lett 1995; 201: 223–226.
Chandler S, Miller KM, Clements JM, et al.Matrix metalloproteinases, tumor necrosis factor and multiple sclerosis: an overview. J Neuroimmunol 1997; 72: 155–161.
Duffy MJ, McCarthy K. Matrix metalloproteinases in cancer: prognostic markers and targets for therapy (review). Int J Oncol 1998; 12: 1343–1348.
Lee MA, Palace J, Stabler G, et al.Serum gelatinase B, TIMP-1 and TIMP-2 levels in multiple sclerosis. A longitudinal clinical and MRI study. Brain 1999; 122: 191–197.
Noble LJ, Donovan F, Igarashi T, et al.Matrix metalloproteinases limit functional recovery after spinal cord injury by modulation of early vascular events. J Neurosci 2002; 22: 7526–7535.
Stetler-Stevenson WG, Hewitt R, Corcoran M. Matrix metalloproteinases and tumor invasion: from correlation and causality to the clinic. Semin Cancer Biol 1996; 7: 147–154.
Matsui Y, Maeda M, Nakagami W, et al.The involvement of matrix metalloproteinases and inflammation in lumbar disk herniation. Spine 1998; 23: 863–869.
de Castro RC, Burns CL, McAdoo DJ, et al.Metalloproteinase increases in the injured rat spinal cord. Neuroreport 2000; 11: 3551–3554.
Duchossoy YS, Arnaud S, Feldblum S. Matrix metalloproteinases: potential therapeutic target in spinal cord injury. Clin Chem Lab Med 2001; 39: 362–367.
Goussev S, Hsu JY, Lin Y, et al.Differential temporal expression of matrix metalloproteinases after spinal cord injury: relationship to revascularization and wound healing. J Neurosurg 2003; 99(suppl 2): 188–197.
Olby N. Current concepts in the management of acute spinal cord injury. J Vet Intern Med 1999; 13: 399–407.
Hoerlein BF. Intervertebral disk disease. In: Oliver JE, Hoerlein BF, Mayhew IG, eds. Veterinary neurology. Philadelphia: WB Saunders Co, 1987; 321–341.
Hoerlein BF. Intervertebral disk disease. In: Hoerlein BF, ed. Canine neurology: diagnosis and treatment. Philadelphia: WB Saunders Co, 1978; 470–560.
Goggin JE, Li A, Franti CE. Canine intervertebral disk disease: characterization by age, sex, breed, and anatomic site of involvement. Am J Vet Res 1970; 31: 1687–1692.
Olby N, Levine J, Harris T, et al.Long-term functional outcome of dogs with severe injuries of the thoracolumbar spinal cord: 87 cases (1996–2001). J Am Vet Med Assoc 2003; 222: 762–769.
Davies JV, Sharp NJ. A comparison of conservative treatment and fenestration for thoracolumbar intervertebral disk disease in the dog. J Small Anim Pract 1983; 24: 721–729.
Denny HR. The lateral fenestration of canine thoracolumbar disk protrusions: a review of 30 cases. J Small Anim Pract 1978; 19: 259–266.
Bergman RL, Inzana KD, Inzana TJ. Characterization of matrix metalloproteinase-2 and -9 in cerebrospinal fluid of clinically normal dogs. Am J Vet Res 2002; 63: 1359–1362.
Takeshita S, Tokutomi T, Kawase H, et al.Elevated serum levels of matrix metalloproteinase-9 (MMP-9) in Kawasaki disease. Clin Exp Immunol 2001; 125: 340–344.
Yokota H, Kumata T, Taketaba T, et al.High expression of 92 kDa type IV collagenase (matrix metalloproteinase-9) in canine mammary adenocarcinoma. Biochim Biophys Acta 2001; 1568: 7–12.
Rosenberg GA, Dencoff JE, Correa N Jr, et al.Effect of steroids on CSF matrix metalloproteinases in multiple sclerosis: relation to blood-brain barrier injury. Neurology 1996; 46: 1626–1632.