Phenotypes of pathologic vertebral endplate degeneration

慢性下腰痛(CLBP)是发病率和社会费用的重要原因。腰间盘是 被认为是主要的疼痛来源，但对椎间盘退化和受伤的机制知之甚少。 历史数据表明，由于以下原因，终板可能是一些导致间盘病变的患者的重要疼痛来源 椎间盘和相邻椎体之间的病理性串扰。此外，我们对NASA宇航员的研究表明 改变脊柱力学和终板的脊柱旁肌肉萎缩加剧了这种病理上的串扰。 正在装车。在过去的资金支持期间，我们将工作重点放在开发有关椎间盘疼痛的新证据上。 机制，并在此基础上，先进的成像工具，是敏感和特异的下腰病理。 我们建立了病理串扰的关键方面的成像生物标志物：1)终板损伤(UTE MRI)； 骨髓水肿和椎旁肌肉萎缩(理想的MRI)；以及椎间盘化学/感染(MRS)。我们也 研究了串扰触发脊椎骨髓损伤的细胞机制(MODIC改变； 我们的数据表明，这是CLBP患者常见的疼痛产生因素。以进一步澄清这些机制 终板损伤和MC的临床相关性，我们现在建议描述MC自然病史的关系 对动物和人类的病因学(炎症和感染)。我们将使用我们已建立的成像系统 将大鼠MC的结构和生物学数据与疼痛严重程度联系起来的生物标记物 人类的脊髓灰质炎进展和椎旁肌萎缩。我们将测试成像生物标志物的假设 终板损伤、椎间盘化学和肌肉萎缩可预测MC的进展和症状严重程度。 提出了三个目标。在目标1中，我们将描述与以下相关的MC机制和自然历史 使用鼠尾模型的病因学(炎症或感染)。在目标2中，我们将对CLBP进行纵向研究 患者检验MC严重程度和进展与终板损伤程度成正比的假设 (这有助于串扰)，以及存在邻近的“Modic Disk”，其中缺血驱动了表达 炎性细胞因子和疼痛相关因子(缺血性、无菌炎症)，或炎性因子 由痤疮丙酸杆菌(感染性炎症)上调。在目标3中，我们将调查 椎旁肌萎缩通过改变加重终板损伤、MC和患者症状 节段对齐(前凸)和节段间力学(动态运动)。总体而言，我们假设 根据椎间盘和脊柱旁肌肉的情况，MC和症状自然病史会有所不同-MC由于 当脊柱旁肌肉质量良好时，无菌炎症会随着时间的推移而消退。或者，MC由于 感染刺激将会进展(因为潜在的感染是持续的)。通过这项工作，我们将验证 一种成像套件，研究人员可以使用它来研究临床队列中的脊柱病理，临床医生可以 用于定位疼痛产生因素，预测未来的症状进程，并改善CLBP患者的护理。

Chronic low back pain (CLBP) is a significant cause of morbidity and societal expense. The intervertebral disc is thought to be a primary pain source, but mechanisms by which discs degenerate and hurt are poorly understood. Historical data suggest that the endplate can be a significant source of pain in some ‘discogenic’ patients due to pathological crosstalk between discs and adjacent vertebra. Further, our studies with NASA astronauts indicate that pathologic crosstalk is exacerbated by paraspinal muscle atrophy that alters spinal mechanics and endplate loading. Over the past funding period, we focused our efforts on developing new evidence for disc pain mechanisms, and based on these, advanced imaging tools that are sensitive and specific for low back pathology. We established imaging biomarkers for key aspects of pathologic crosstalk: 1) endplate damage (UTE MRI); bone marrow edema and paraspinal muscle atrophy (IDEAL MRI); and disc chemistry/infection (MRS). We also investigated cellular mechanisms by which crosstalk triggers vertebral bone marrow lesions (Modic changes; MC) that our data indicate are a common pain generator in CLBP patients. To further clarify the mechanisms and clinical relevance of endplate damage and MC, we now propose to characterize MC natural history in relation to etiology (inflammation versus infection) in an animals and humans. We will use our established imaging biomarkers to link architectural and biological data from MC induced in rats, to pain severity in association with MC progression and paraspinal muscle atrophy in humans. We will test the hypothesis that imaging biomarkers of endplate damage, disc chemistry, and muscle atrophy forecast MC progression and symptom severity. Three aims are proposed. In Aim 1 we will characterize MC mechanisms and natural history in relation to etiology (inflammation or infection) using a rat-tail model. In Aim 2 we will conduct a longitudinal study of CLBP patients to test the hypothesis that MC severity and progression is proportional to the extent of endplate damage (which facilitates crosstalk), and the presence of an adjacent ‘Modic disc’, where ischemia drives the expression of inflammatory cytokines and pain-related factors (ischemic, sterile inflammation), or where inflammatory factors are upregulated by Propionibacteria acnes (infectious inflammation). In Aim 3 we will investigate the role paraspinal muscle atrophy toward exacerbating endplate damage, MC, and patient symptoms via altered segmental alignment (lordosis) and intersegmental mechanics (dynamic motion). Overall, we hypothesize that MC and symptom natural history will vary depending on both disc and paraspinal muscle condition - MC due to a sterile inflammation will resolve over time when paraspinal muscle quality is good. Alternatively, MC due to an infections stimulus will progress (since the underlying infection is ongoing). Through this work, we will validate an imaging suite that researchers can use to study the spine pathologies in clinical cohorts, and clinicians can use to localize pain generators, predict the future course of symptoms, and improve care of CLBP patients.