Interaction of mechanical and inflammatory signals in disc matrix preservation

描述（由申请人提供）：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起着重要作用。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基质破坏或修复。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，并开始揭示导致这些影响的途径。初步数据表明，基因表达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。这项工作将验证短时间机械刺激对炎症刺激的保护作用将通过降低分解代谢蛋白的表达、活性和核信号传导来反映。同样，我们预计由炎症刺激引起的分解代谢蛋白的表达、活性和核信号会因长时间的机械刺激而加剧。此外，我们预计通过核因子κ B （NFkB）途径的信号传导将对这些效应至关重要，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将纤维环细胞暴露于张力和髓核细胞暴露于压缩，作为研究炎症和机械信号通路相互作用的起点。我们选择了1)已被证明对椎间盘基质完整性很重要的关键结果测量；2)受到炎症和机械刺激的影响；3)证明了它们的基因表达随选择的加载方案而变化。这些研究将深入了解先前观察到的基因表达变化的生物学意义，并揭示炎症和机械刺激对椎间盘基质稳态影响的合理机制。预计这项工作将导致未来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途径之间的协同作用，这些途径可能在未来的治疗中被潜在地利用。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。

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.