GDF-5 Regulation in Intervertebral Disc Degeneration

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DESCRIPTION (provided by applicant): Back pain resulting from intervertebral disc degeneration is a major health problem in western societies. Current therapies are aimed at gaining symptomatic relief. The searches for biologically based treatments that can halt, retard or reverse the effects of disc degeneration are being sought. Growth Differentiation Factor-5 (GDF-5), an important growth factor for joint formation and chondrocyte development, deficiency of which would lead to early degeneration of intervertebral disc, deserves a detailed investigation. However, the temporal expression of GDF-5 in disc degeneration is unknown and there are few studies on GDF-5 therapy for disc degeneration. We hypothesize that GDF-5 plays an important role in disc repair and GDF-5 therapy to metabolically impaired cells in degenerative IVD can restore the disc matrix and structure. In Aim 1, we will define temporal expression and distribution of GDF-5 and extracellular proteins with immunolocalization and real-time RT-PCR. Correlation between GDF-5 expression and degree of disc degeneration will be elucidated. This information is essential to understand the role of GDF-5 in disc degeneration in order for a well informed decision to be made to use GDF-5 as a therapeutic agent for early stage disc injury or degeneration, In Aim 2A, we will use the GDF-5 deficient mouse model which provides a unique opportunity to define the role of GDF-5 in IVD repair by local correction of a genetic defect. The discs of the GDF-5 deficient mouse have been characterized by our research group and were shown to have histological and biochemical abnormalities similar to degenerative disc. Our in vitro studies support the hypothesis that GDF-5 therapy can normalize some parameters of disc cell metabolism. It is hypothesized that regional GDF-5 gene therapy will normalize the MRI appearance, histology, and biochemistry of the intervertebral disc in the GDF-5 deficient mouse. In Aim 2B, a well-developed disc degeneration model will be used to investigate whether GDF-5 therapy will retard or reverse disc degeneration that is induced by other pathogenic factors in addition to therapeutic effects on GDF-5 deficiency-induced disc degeneration. If successful in achieving meaningful repair, this project will help investigators make significant strides towards enabling disc repair in humans.