Experimental chemonucleolysis with recombinant human matrix metalloproteinase 7 in human herniated discs and dogs

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Haro H, Nishiga M, Ishii D, et al. 

Spine J 2014;14:1280-1290.

BACKGROUND CONTEXT: Chemonucleolysis 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 Once chymopapain had been approved as a chemonucleolysis drug, it was withdrawn because of serious complications.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. PURPOSE: The 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 DESIGN: The study design is the experimental study using human herniated discs and enzyme substrates in vitro and dogs in vivo. METHODS: The 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. RESULTS: Recombinant 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. CONCLUSIONS: This 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.