Chondroitinase ABC-induced intervertebral disc degeneration is minimized when the enzyme is co-injected with osteogenic protein-1: an in vivo study using a rabbit model

Abstract

Purpose of study: Chondroitinase-ABC (C-ABC) is commonly used to degrade the chondroitin sulfate and dermatan sulfate chains of proteoglycans. In some countries, C-ABC, injected intradiscally, shows promise as a chemonucleolytic agent. However, the removal of glycosaminoglycans may lead, over the long-term, to significant degradation of the injected intervertebral disc (IVD). Osteogenic protein-1 (OP-1) has been shown to stimulate IVD matrix synthesis in vitro and, thus, may be useful in inhibiting and/or slowing down IVD matrix degradation in vivo. The purpose of this study was to monitor the effect of recombinant human OP-1 (rhOP-1) on the in vivo repair of IVDs co-injected with C-ABC.Methods used: Twenty-four New Zealand White rabbits (3 kg) were divided equally into four groups (control vehicle; C-ABC [10 mU] alone; rhOP-1 [100 μg] alone; or C-ABC + OP-1 [10 mU+100 μg, respectively] co-injected). The assigned agents (10 μl/disc) were injected into three levels of IVDs for each rabbit in each group. Radiographs of the lumbar spine were taken every 2 weeks after in the injections. At 4 or 12 weeks after the injections, three rabbits in each group were euthanized and the IVDs assessed biochemically and histologically.of findings: Significant disc space narrowing was observed 2 weeks after the injection of either C-ABC or C-ABC + OP-1, but not after injection of the control vehicle. In the C-ABC group, this narrowing was sustained for up to 12 weeks (4 weeks, 77 ± 11%; 12 weeks, 75 ± 8%). In the C-ABC + OP-1 group, the disc height index (DHI) had begun to return toward normal after 4 weeks (C-ABC vs. C-ABC + OP-1, p<.001) and was no longer significantly different from the control group at 12 weeks (control, 86% ± 6%; C-ABC + OP-1; 92% ± 12%). Biochemical and histological analyses supported those findings (Fig. 1).Relationship between findings and existing knowledge: Importantly, the addition of OP-1 to the intradiscally injected solution did not interfere with C-ABC–induced chemonucleolysis. Furthermore, measurement of DHI showed that OP-1 was very effective in subsequently stimulating matrix repair.Overall significance of findings: These in vivo findings illustrate the potential of OP-1 to promote nucleus pulposus regeneration in humans after chemonucleolysis.Disclosures: Device or drug: recombinant human osteogenic protein-1. Status: investigational.Conflict of interest: Howard An, and Koichi Masuda, grant research support: Stryker Biotech.