Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 0G1, Canada; McGill Scoliosis and Spine Research Group, McGill University, Montreal, Quebec H3A 1G1, Canada; Faculty of Medicine, Department of Surgery, Orthopaedic Research Lab, McGill University, Montreal, Quebec H3A 1G1, Canada.
Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 0G1, Canada; McGill Scoliosis and Spine Research Group, McGill University, Montreal, Quebec H3A 1G1, Canada; Faculty of Dentistry, McGill University, Montreal, Quebec H3A 1G1, Canada.
EBioMedicine. 2019 May;43:487-500. doi: 10.1016/j.ebiom.2019.04.032. Epub 2019 Apr 30.
Low back pain (LBP) is the leading global cause of disability and is associated with intervertebral disc degeneration (DD) in some individuals. However, many adults have DD without LBP. Understanding why DD is painful in some and not others may unmask novel therapies for chronic LBP. The objectives of this study were to a) identify factors in human cerebrospinal fluid (CSF) associated with chronic LBP and b) examine their therapeutic utility in a proof-of-concept pre-clinical study.
Pain-free human subjects without DD, pain-free human subjects with DD, and patients with chronic LBP linked to DD were recruited and lumbar MRIs, pain and disability levels were obtained. CSF was collected and analyzed by multiplex cytokine assay. Interleukin-8 (IL-8) expression was confirmed by ELISA in CSF and in intervertebral discs. The SPARC-null mouse model of progressive, age-dependent DD and chronic LBP was used for pre-clinical validation. Male SPARC-null and control mice received systemic Reparixin, a CXCR1/2 (receptors for IL-8 and murine analogues) inhibitor, for 8 weeks. Behavioral signs of axial discomfort and radiating pain were assessed. Following completion of the study, discs were excised and cultured, and conditioned media was evaluated with a protein array.
IL-8 was elevated in CSF of chronic LBP patients with DD compared to pain-free subjects with or without DD. Chronic inhibition with reparixin alleviated low back pain behaviors and attenuated disc inflammation in SPARC-null mice.
These studies suggest that the IL-8 signaling pathway is a viable therapy for chronic LBP. FUND: Supported by NIH, MMF, CIHR and FRQS.
腰痛（LBP）是全球导致残疾的主要原因，在某些个体中与椎间盘退变（DD）有关。然而，许多成年人有 DD 但没有 LBP。了解为什么 DD 在某些人身上会引起疼痛而在其他人身上不会，可能会为慢性 LBP 揭示新的治疗方法。本研究的目的是：a）确定与慢性 LBP 相关的人脑脊液（CSF）中的因素；b）在概念验证性临床前研究中检验其治疗效果。
招募无腰痛（LBP）的无 DD 疼痛的健康受试者、无腰痛（LBP）的有 DD 疼痛的健康受试者和与 DD 相关的慢性 LBP 患者，并获取腰椎 MRI、疼痛和残疾程度。收集 CSF 并通过多重细胞因子分析进行分析。通过 ELISA 确认 CSF 和椎间盘中的白细胞介素-8（IL-8）表达。使用 SPARC 缺失小鼠模型进行慢性进行性、年龄依赖性 DD 和慢性 LBP 的临床前验证。雄性 SPARC 缺失和对照小鼠接受全身性 Reparixin（一种 CXCR1/2（IL-8 和鼠类似物的受体）抑制剂）治疗 8 周。评估轴向不适和放射痛的行为迹象。研究完成后，切除并培养椎间盘，并使用蛋白质阵列评估条件培养基。
与无 DD 疼痛的健康受试者或有 DD 疼痛的健康受试者相比，慢性 LBP 患者的 CSF 中 IL-8 升高。慢性抑制 Reparixin 可缓解 SPARC 缺失小鼠的腰痛行为并减轻椎间盘炎症。
这些研究表明，IL-8 信号通路是治疗慢性 LBP 的可行方法。资金：由 NIH、MMF、CIHR 和 FRQS 资助。
