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

描述(申请人提供)：超生理活动、衰老和遗传因素可能会引发椎间盘退变，其特征是但不限于水分丧失、基质成分浓度改变、机械僵硬和最终的背部疼痛。过多的机械负荷作用在尾盘上，类似于用力举起所产生的负荷，会诱发椎间盘退变的各个方面。然而，使用机械载荷进行退变的研究主要集中于描述退变对椎间盘结构及其基质成分的影响，而对其潜在的机制缺乏深入的了解(S)。此外，椎间盘退变的风险随着年龄的增长而增加，因此，评估老化对有害负荷反应的影响是很重要的。β-连环蛋白受典型的Wnt途径调节，推测参与了椎间盘的分解代谢。胞外Wnt配体是 转录因子β-连环蛋白的上游调节因子，它积累在人类退变的椎间盘细胞中，以及已知有与年龄相关的退变倾向的犬类细胞。抑制浸泡在炎性细胞因子中的软骨细胞中的β-连环蛋白信号可以减轻分解代谢标记物的表达，这表明靶向这一途径可能具有治疗潜力。我们将结合我们的经验和小鼠负载模型和遗传工具来确定β-连环蛋白激活在机械负载诱导的椎间盘退变中的作用。机械超载的结构、细胞和分子水平的后果：一只报告小鼠的β-连环蛋白被激活，一只条件基因敲除小鼠的小鼠在青壮年和老年小鼠中被激活。这项研究将通过确定β-连环蛋白在椎间盘退变模型中的参与来影响椎间盘机械生物学领域，并有助于提供一种机制，在此基础上开发能够抑制或预防椎间盘退变的治疗方法。

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.