The prevalence of musculoskeletal impairments of the spine in the U.S. is estimated to be greater than 18 million--many of which are the direct or indirect result of intervertebral disc degeneration (IDD). The limited available technology for the treatment of the pathologic and disabling conditions arising from IDD generally is highly invasive (e.g., surgical discectomy and fusion), manifesting a certain degree of complications and unsatisfactory clinical outcomes. To date, little effort has been made to directly treat the underlying problem of disc degeneration--a chronic process characterized in part by progressive loss of proteoglycans leading to disc dehydration, alterations in disc structure, and impaired disc function. Recent advancements in molecular biology have made it possible to contemplate treating the intervertebral disc itself at a molecular level to prevent or delay the progression of IDD. We hypothesize that imbalance in the synthesis and catabolism of certain critical extracellular matrix (ECM) components (a final common pathway in IDD) can be mitigated by the transfer of genes to intervertebral disc cells encoding factors that modulate synthesis and catabolism of these ECM components--thereby improving disc composition, structure, and ultimately function. The proposed study will test the efficacy of adenovirus-mediated delivery of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) genes in interrupting the degenerative cascade in a novel rabbit model of disc degeneration, using functional outcomes and MRI to assess preservation of disc composition, structure, and function. The significance of this study includes an improved basic science understanding of the pathogenesis and pathophysiology of IDD, as well as the identification of novel therapeutic approaches to the clinical treatment of IDD.
| Vo, Nam V; Hartman, Robert A; Yurube, Takashi et al. (2013) Expression and regulation of metalloproteinases and their inhibitors in intervertebral disc aging and degeneration. Spine J 13:331-41 |
| Studer, Rebecca K; Gilbertson, Lars G; Georgescu, Helga et al. (2008) p38 MAPK inhibition modulates rabbit nucleus pulposus cell response to IL-1. J Orthop Res 26:991-8 |
| Studer, Rebecca K; Aboka, Alex M; Gilbertson, Lars G et al. (2007) p38 MAPK inhibition in nucleus pulposus cells: a potential target for treating intervertebral disc degeneration. Spine (Phila Pa 1976) 32:2827-33 |
