Abstract ID: A6
Abstract Title: Gelatinase A Inhibition Attenuates Extracellular Matrix Remodeling and Cell Proliferation and Migration in Rats. Relevance to the Pathogenesis and Management of Chronic Pain.
Poster Type: Discussion
ABSTRACT BODY
Introduction: Matrix metalloproteinases (MMP) are the key enzymes in the pathogenesis of osteoarthritis and inflammatory arthritis. Inhibition of the matrix metalloproteinases has been postulated to block metastasis invasion and to play an important role in the pathogenesis of both non-cancer and cancer chronic pain.
Gelatinase A (matrix metalloproteinase-2) participates in the degradation of the extracellular matrix components in a variety of arthritis. Gelatin zymography revealed that the activaty of Gelatinase A (matrix metalloproteinase-2) in synovial fluid joints of gouty arthritis was associated with the local arthritis activity scores (LAS) (p < 0.001) and correlated well with the neutrophil counts in the synovial fluid as well (p < 0.001). Matrix metalloproteinases have been implicated in the excessive breakdown of extracellular matrix components during disc degeneration. The activity of Gelatinase A (matrix metalloproteinase-2) was increased in the ovine model of intervertebral disc degeneration one of the major causes of the low back pain in humans.
Chronic constriction injury to peripheral nerve causes a painful neuropathy in association with a process of axonal degeneration and endoneural remodeling that involves macrophage recruitment and local increase in matrix metalloproteinases, including Gelatinase A (matrix metalloproteinase-2) activity with a possible relevance to the pathogenesis of neuropathic pain.
Our study determines the long term effect of metalloproteinase inhibition on extracellular matrix remodeling, cell proliferation and migration in rats. The study was performed on the common carotid artery model because of the good accessibility and reliable injury assessment techniques of this model in comparison to articular cartilage. It addresses the direct effect of the mechanical injury on matrix metalloproteinase 2 activity using the methods developed in the previous study.
Design: A long term prospective randomized study.
Setting: Research laboratory and animal facility.
Interventions: Intraperitoneal injections of metalloproteinase inhibitor.
Methods: 91 slides from the the common carotid artery of Sabra rats treated with the metalloproteinase inhibitor underwent immunohistochemical staining and histomorphometric evaluation
Results: The absolute number of the BrDU stained cells was significantly lower in the neointima 14, 25, and 75 days after the injury in the group which received combined treatment vs. the control group (p=0.0001, 0.001 and 0.01 respectively). The mean relative intensity of the MMP-2 bands (100±13), measured by computerized densitometry was significantly greater than in control group than in the treated animals.
Conclusion: We found that MMP inhibition resulted in a significant decrease in the cell proliferation and the remodeling of the extracellular matrix up to 2½ months after the MMP injection versus untreated control group and that these effects were associated with a marked reduction in MMP-2 activity. We strongly advocate testing of matrix metalloproteinase inhibitors in larger animals and in the clinical setting as a potential disease modifying agent for non-cancer and cancer chronic pain syndromes.
ATTACHED FILES
Reg Anesth Pain Med 2004; 29(2):A6