Role of Mechanical Forces on Beta-Catenin of Aged Intervertebral Discs

Washington University, Saint Louis MO

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Abstract

DESCRIPTION (provided by applicant): Supra-physiological activity, aging and genetic factors may initiate intervertebral disc degeneration, which is characterized by, but not limited to, loss f hydration, altered concentrations of matrix constituents, mechanical stiffening and ultimately back pain. Excessive mechanical loads on tail discs, as analogous to those engendered by strenuous lifting, induce aspects of disc degeneration. However, studies of degeneration using mechanical loading focus on describing the consequences to disc structure and its matrix constituents with little insight into the underlying mechanism(s). Further, the risk of disc degeneration increases with age and therefore, it is important to evaluate the influence of aging on the response to deleterious loading. beta-Catenin is regulated by the canonical Wnt pathway and is putatively involved in the catabolism of intervertebral discs. Extracellular Wnt ligands are upstream regulators of transcription factor beta-catenin, which accumulates in the cells of human degenerated discs, and cells from canines known to have an age-related propensity for degeneration. Suppression of beta-catenin signaling in chondrocytes immersed in inflammatory cytokines mitigates the expression of catabolic markers, suggesting that targeting this pathway may have therapeutic potential. We will combine our experience with murine loading models and genetic tools to determine the role of beta-catenin activation in disc degeneration induced by mechanical loading. The structural-, cellular- and molecular- level consequences of mechanical overloading in a reporter mouse of beta-Catenin activation and a conditional knockout mouse of beta-catenin in young-adult and aged mice. This research will impact the field of intervertebral disc mechano-biology by identifying the involvement of beta-catenin in a model of disc degeneration and help provide a mechanism upon which to develop treatments capable of curbing or preventing disc degeneration.