Study 1. The Roles of IL-19, IL-20 on Intervertebral Disc Herniation and Degenerative Lumbar Spondylolisthesis The inflammatory reaction after intervertebral disc herniation (HIVD) was considered as the major cause of low back pain and sciatica. IL-19 and IL-20, members of IL-10 family, are involved in various inflammatory diseases. However, little is known on how IL-19 and IL-20 affect the inflammation, healing process, and degeneration of spine after intervertebral disc injury. We reported the expression of IL-20 and its receptors in the primarily cultured disc cells as well as in human herniated intervertebral disc (HIVD) tissues. Disc cells express IL-20 receptors and are targeted by IL-20. In vitro, IL-1β induced the expression of IL-20, and IL-20 combined with IL-1β induced the expression of various cytokines, chemokines, angiogenetic factors, and matrix metalloproteinases (MMPs) in human disc cells. Therefore, IL-20 together with IL-1β enhances the inflammatory process after disc injury, and IL-20 may contribute to the pathogenesis of HIVD. Degenerative lumbar spondylolisthesis (DLS) results from disc injury, which usually occurs at the L4/L5 level after the facet-joint locking mechanism fails. The etiology of DLS is multifactorial, and includes spinal instability, neurological compromise and inflammation. In clinical practice, symptoms are not well correlated with the severity of degeneration and neural compression on MRIs of patients with DLS. Inflammation may play an important role in the pathogenesis of DLS; however, expression of IL-19 and IL-20 and their pathophysiological function in DLS has not been explored. Thus, we explored if IL-19 and IL-20 were associated with DLS. We found that IL-19, IL-20, IL-20R1 and IL-20R2, TNF-α, IL-1β and MCP-1 were co-localized in tissue samples of degenerated discs, facet joints, and ligamentum flavum retrieved from patients with DLS. The expression of IL-19 and IL-20 is associated with the expression of the inflammatory cytokines, TNF-α and IL-1β and the chemokines, MCP-1 and IL-8. In vitro, IL-19 and IL-20 induced the expression of proinflammatory cytokines, chemokine, and angiogenesis under CoCl2-mimicked hypoxia condition in the primarily cultured human disc cells, which isolated from degenerated disc tissues of patients with DLS. Therefore, IL-19 and IL-20 may contribute to the inflammatory process in discs, facet joints, and the ligamentum flavum in patients with DLS；IL-19 and IL-20 may be involved in the pathogenesis of DLS. Study 2. The in vivo Biological Effects of Intra-discal RhBMP-2 on the Injured Intervertebral Disc RhBMP-2, a potent osteoinductive and chondroinductive factor, has been approved for use in human anterior spinal fusion and can promote cartilage repair. We found that BMP-2 can be expressed in the human herniated disc specimen. However, the in vivo response of intra-discal rhBMP-2 on the injured IVDs is not clear. We found that various degrees of degenerative change around the injured disc space in our rabbit disc injury model. More severe spondylosis, such as spur formation, was found in the groups treated with rhBMP-2. The pathological findings revealed that rhBMP-2 promotes angiogenesis and inflammation after disc injury; which are known as the first two stages of bone incorporation for fusion. Therefore, rhBMP-2 might contribute to the injury response, healing process and subsequent degeneration after disc injury. Study 3. Factors Affecting Disability and Physical Function in Degenerative Lumbar Spondylolisthesis Axially-loaded magnetic resonance image (MRI) is a useful diagnostic tool, enabling detection of dynamic or occult changes of spinal disorders by simulating the upright position under normal gravity and mimicking the condition of axial compression in the lumbar spine. Except the roles of IL-19 and IL-20 in the inflammation process of degenerative lumbar spondylolisthesis (DLS), we aimed to further analyze the critical biomechanical factors responsible for the disability and physical function of patients with DLS using axially-loaded MRI, and to investigate the effect of axial loading on the morphology of the spine and the spinal canal. All patients underwent unloaded and axially-loaded MRI. We measured the predictors on MRI, including the differences of disc height (DH), sagittal translation (ST), segmental angulation (SA), and dural sac cross-sectional area (DCSA) at L4-5 between the unloaded and axially-loaded condition, as well as pre-load and post-load lumbar lordotic angles (LLA) at L1-5. We discovered that angular instability is correlated with physical disability and physical function for patients with L4-5 DLS in an axially-loaded magnetic resonance image (MRI); the post-load lumbar lordotic curve angle is also well correlated with physical function for patients with L4-5 DLS. Segmental angulation of L4-5 can be a good indicator of disability in patients with L4-5 DLS. In conclusion, we discovered that IL-19, IL-20, and BMP-2 may be the key factors to modulate inflammation, healing process and degeneration of spine after intervertebral disc injury. Besides, we also discovered that angular instability of intervertebral disc is correlated with physical disability and physical function for patients with L4-5 DLS.
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