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Experimental chemonucleolysis with recombinant human matrix metalloproteinase 7 in human herniated discs and dogs |
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| Authors: | Hirotaka Haro Miyuki Nishiga Daisuke Ishii Takasumi Shimomoto Tsuyoshi Kato Osami Takenouchi Satoshi Koyanagi Tetsuro Ohba Hiromichi Komori |
| Affiliation: | 1. Department of Orthopaedic Surgery, Graduate School of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan;2. Teijin Institute for Bio-Medical Research, Teijin Pharma Limited, Tokyo, Japan;3. Department of Orthopaedic and Spinal Surgery, Tokyo Medical and Dental University, Tokyo, Japan;4. The Chemo-Sero-Therapeutic Research Institute (Kaketsuken), Kumamoto, Japan;5. Department of Orthopaedic Surgery, Yokohama City Minato Red Cross Hospital, Kanagawa, Japan;1. Section of Behavioral Sciences, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima 739-8521, Japan;2. Department of Agrobiological Science, Faculty of Agriculture, Ehime University, Matsuyama 790-8566, Japan;3. Taskforce to study Resistance Emergence and Antimicrobial development Technology (TREAT), The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231;4. Division of Infectious Diseases, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231;5. Structural Enzymology and Thermodynamics Group, Department of Biophysics and Biophysical Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205;12. Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205;6. National Synchrotron Light Source II, Brookhaven National Laboratory, Upton, New York 11973;3. From the Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus, Denmark,;4. the Interdisciplinary Nanoscience Center (iNANO), DK-8000 Aarhus, Denmark,;5. the Proteolysis Laboratory, Department of Structural Biology (“María de Maeztu” Unit of Excellence), Molecular Biology Institute of Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona Science Park, c/Baldiri Reixac 15-21, 08028 Barcelona, Catalonia, Spain, and;6. DuPont Industrial Biosciences, DK-8220 Brabrand, Denmark |
| Abstract: | Background contextChemonucleolysis has been proposed as a less invasive technique than surgery for patients with lumbar disc herniation. Once chymopapain had been approved as a chemonucleolysis drug, it was withdrawn because of serious complications. A novel agent with fewer complications would be desirable.PurposeThe purpose of this study was to investigate the effects of recombinant human matrix metalloproteinase 7 (rhMMP-7) in experimental chemonucleolysis in vitro and in vivo and examine its effects on tissue damage.Study designThe study design is the experimental study using human herniated discs and enzyme substrates in vitro and dogs in vivo.MethodsThe effects of rhMMP-7 on the degradation of human herniated discs were examined by measuring the wet weight in vitro. The correlations between the decrease in wet weight by rhMMP-7 and the conditions associated with herniated discs were also analyzed. The effects of rhMMP-7 on the proteoglycan and water contents were respectively examined with alcian blue staining and T2-weighted magnetic resonance imaging at 7 days after intradiscal injection in dogs. The distribution of [125I]-labeled rhMMP-7 was investigated by autoradioluminography at 7 days after intradiscal injection in dogs. An epidural injection study with rhMMP-7 was performed to evaluate the effects on the tissue damage around the discs at 1 and 13 weeks after the treatment in dogs. The Type 1 and 2 collagen cleavage rates were measured and compared with those of aggrecan in vitro.ResultsRecombinant human matrix metalloproteinase 7 concentration dependently decreased the wet weight of herniated discs in vitro. The decrease in wet weight of the discs by rhMMP-7 did not significantly correlate with the conditions associated with herniated discs. Intradiscal injection of rhMMP-7 reduced the proteoglycan and water contents, with an increase in the serum keratan sulfate levels. Radioactivity of [125I]-labeled rhMMP-7 was detected in the nucleus pulposus and annulus fibrosus but not in the muscle. Epidural injection of rhMMP-7 had no effect on the injection site or the nerve tissues. The Type 1 and 2 collagen cleavage rates of rhMMP-7 were 1,000-fold weaker than those of aggrecan.ConclusionsThis study demonstrated experimental chemonucleolysis with rhMMP-7 in vitro and in vivo. The effects of rhMMP-7 were not affected by the conditions associated with herniated discs. The epidural injection study together with the autoradioluminography and in vitro enzyme assay suggests that intradiscal injection of rhMMP-7 may not induce tissue damage around the discs because of its distribution and substrate selectivity. Recombinant human matrix metalloproteinase 7 may be a novel and promising chemonucleolysis agent. |
| Keywords: | Chemonucleolysis Matrix metalloproteinase 7 Intervertebral disc Herniation Minimally invasive treatment Herniated disc resorption |
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