Interaction of mechanical and inflammatory signals in disc matrix preservation

描述（由申请方提供）：多种因素导致椎间盘疾病中观察到的基质降解。其中，炎症和机械信号通路似乎在维持椎间盘基质的分解代谢和合成代谢平衡中发挥重要作用。这项工作的目的是揭示这些关键途径如何相互作用，导致净矩阵分解或修复。具体来说，本研究的目的是评估椎间盘细胞对炎症和机械刺激的反应，并开始解开这些影响的途径。初步数据表明，基因表达的变化反映了张力和压缩的保护和分解代谢水平，机械刺激的持续时间是决定细胞反应的最重要因素。拟议的工作将测试这一假设，即短时间机械刺激对炎症刺激的保护作用将反映在减少分解代谢蛋白的表达，活性和核信号。类似地，我们预期由炎症刺激引起的分解代谢蛋白表达、活性和核信号传导将被长时间的机械刺激加剧。此外，我们预计通过核因子κ B（NF κ B）途径的信号传导对这些作用至关重要，因为它涉及炎症和机械信号传导。我们建议利用体外模型系统，暴露纤维环细胞的张力和髓核细胞的压缩作为一个起点，检查炎症和机械信号通路的相互作用。我们选择了关键的结局指标，1）已被证明对椎间盘基质完整性很重要; 2）受炎症和机械刺激的影响; 3）证明了其基因表达对所选负荷方案的反应变化。这些研究将提供深入了解以前观察到的基因表达变化的生物学意义，并揭示合理的机制，炎症和机械刺激对椎间盘基质的稳态的影响。预计这项工作将导致未来的研究检查炎症和机械刺激的生物学结果以及对椎间盘退变的影响。这项工作的长期目标是确定关键控制点和可能在未来治疗中利用的途径之间的协同作用。这将通过解决椎间盘疾病的基质完整性产生深远的影响，这对于考虑退行性椎间盘疾病的生物学方法至关重要。 公共卫生相关性：腰痛是患者就医的第二大原因，也是肌肉骨骼相关残疾索赔的最高原因。椎间盘退变和相关的生物力学变化是腰痛最常见的原因之一。开发新的和更有效的治疗方案将需要更好地了解椎间盘退变的机制，如本提案所述。

DESCRIPTION (provided by applicant): Multiple factors contribute to the matrix degradation observed in intervertebral disc disease. Among these, inflammatory and mechanical signaling pathways appear to play a significant role in maintaining the catabolic and anabolic balance of the disc matrix. It is the objective of this work to uncover how these critical pathways interact to result in net matrix breakdown or repair. Specifically, the aims of this research are to evaluate the response of intervertebral disc cells to inflammatory and mechanical stimuli and begin to unravel the pathways responsible for these effects. Preliminary data have demonstrated gene expression changes reflecting both protective and catabolic levels of both tension and compression, with duration of mechanical stimuli being the most significant factor in determining the cellular response. The proposed work will test the hypothesis that the protective effects of short duration mechanical stimulation against inflammatory stimuli will be reflected in decreased catabolic protein expression, activity and nuclear signaling. Similarly, we expect that catabolic protein expression, activity, and nuclear signaling caused by inflammatory stimulus will be exacerbated by prolonged mechanical stimulation. In addition, we expect that signaling through the nuclear factor kappa B (NFkB) pathway will be critical to these effects as it is involved in both inflammatory and mechanical signaling. We propose to utilize in vitro model systems to expose annulus fibrosus cells to tension and nucleus pulposus cells to compression as a starting point to examine the interaction of inflammatory and mechanical signaling pathways. We have chosen key outcomes measures which 1) have been shown to be important in disc matrix integrity; 2) are affected by inflammatory and mechanical stimuli; and 3) demonstrated changes in their gene expression in response to the chosen loading regimens. These studies will provide insight into the biological significance of the previously observed gene expression changes, and uncover plausible mechanisms for the effects of inflammatory and mechanical stimuli on disc matrix homeostasis. It is anticipated that this work will lead to future studies examining the biologic outcomes of inflammatory and mechanical stimuli and the effects on disc degeneration. It is the long term goal of this work to identify key control points and synergy between the pathways which could potentially be exploited in future therapeutics. This would have profound impact by addressing the matrix integrity of intervertebral disc disease, which is critical in considering biological approaches to degenerative disc disease. PUBLIC HEALTH RELEVANCE: Low back pain is the second leading cause of patients seeking medical attention, and the highest reason for musculoskeletal related disability claims. Intervertebral disc degeneration and the associated biomechanical changes are among the most common causes of low back pain. Developing novel and more efficacious treatment options will require an improved understanding of the mechanisms involved in intervertebral disc degeneration, as outline in this proposal.