An in vivo model of ligamentum flavum hypertrophy from early-stage inflammation to fibrosis.

Abstract

Multi-joint disease pathologies in the lumbar spine, including ligamentum flavum (LF) hypertrophy and intervertebral disc (IVD) bulging or herniation contribute to lumbar spinal stenosis (LSS), a highly prevalent condition characterized by symptomatic narrowing of the spinal canal. Clinical hypertrophic LF is characterized by a loss of elastic fibers and increase in collagen fibers, resulting in fibrotic thickening and scar formation. In this study, we created an injury model to test the hypothesis that LF needle scrape injury in the rat will result in hypertrophy of the LF characterized by altered tissue geometry, matrix organization, composition and inflammation. An initial pilot study was conducted to evaluate effect of needle size. Results indicate that LF needle scrape injury using a 22G needle produced upregulation of the pro-inflammatory cytokine Il6 at 1 week post injury, and increased expression of Ctgf and Tgfb1 at 8 weeks post injury, along with persistent presence of infiltrating macrophages at 1, 3, and 8 weeks post injury. LF integrity was also altered, evidenced by increases in LF tissue thickness and loss of elastic tissue by 8 weeks post injury. Persistent LF injury also produced multi-joint effects in the lumbar IVD, including disc height loss at the injury and adjacent to injury level, with degenerative IVD changes observed in the adjacent level. These results demonstrate that LF scrape injury in the rat produces structural and molecular features of LF hypertrophy and IVD height and histological changes, dependent on level. This model may be useful for testing of therapeutic interventions for treatment of LSS and IVD degeneration associated with LF hypertrophy.