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Investigating Enzyme-Induced Intervertebral Disc Degeneration using High Doses of Catabolic Enzymes

This study explores the role of high-temperature requirement serine protease A1 (HTRA1) in intervertebral disc degeneration (IDD), testing the hypothesis that clinically-relevant catabolic enzymes could induce a shift from anabolic to catabolic metabolism. A model of enzyme-induced IDD was developed, utilizing three enzymes (HTRA1, ADAMTS-4, and MMP-3) at approximately 1000x hyper-physiological doses. Histological analysis showed that while enzyme concentrations induced a catabolic response at the RNA level, no clear degenerative patterns or significant cavity formation were observed after 8 days of culture.

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Investigating Enzyme-Induced Intervertebral Disc Degeneration using High Doses of Catabolic Enzymes

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  1. Introduction High temperature requirement serine protease A1 (HTRA1) has been associated as a potential gene for IDD in human gene association study [1, 2]. Hypothesis. Injection of clinically-relevant catabolic enzymes will induce a shift from anabolic to catabolic metabolism. The aim was to develop a model of enzyme-induced IDD that could be used for efficient investigation of therapeutic treatment options in order to better mimic the clinical outcome of IDD in humans. Three enzymes were tested in a first approach (HTRA1, ADAMTS-4 and MMP-3) at ~1000 x hyper-physiological doses. [1] A. N. Tiaden, M. Klawitter, V. Lux, A. Mirsaidi, et al., J Biol Chem 287, 21335-45 (2012). [2] T. Urano, K. Narusawa, S. Kobayashi, M. Shiraki, et al., J Bone Miner Metab 28, 220-6 (2010).

  2. Result: Histology 6µm section undecalcified MTC Pircosirius R Saf O fast green

  3. Conclusion • Enzyme concentrations at about a factor 1,000 x higher than found at physiological level induced a catabolic response at the RNA level (ADMTS-4 and MMP-13). • However, no evidence for a clear degenerative pattern could be found and there was no evidence for a cavity comparable to papain (biochemistry and histology) after 8 days of culture. • $$$ Costs of enzymes (MMP-3 and ADAMTS-4) are very high compared to more catabolic enzymes such as papain and trypsin and degenerate effects are too modest.

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