Leni & Peter May Dept. of Orthopaedics, Mount Sinai School of Medicine, New York, New York, United States of America.
PLoS One. 2013 May 17;8(5):e64302. doi: 10.1371/journal.pone.0064302. Print 2013.
Diabetes and low back pain are debilitating diseases and modern epidemics. Diabetes and obesity are also highly correlated with intervertebral disc (IVD) degeneration and back pain. Advanced-glycation-end-products (AGEs) increase reactive-oxygen-species (ROS) and inflammation, and are one cause for early development of diabetes mellitus. We hypothesize that diabetes results in accumulation of AGEs in spines and associated spinal pathology via increased catabolism. We present a mouse model showing that: 1) diabetes induces pathological changes to structure and composition of IVDs and vertebrae; 2) diabetes is associated with accumulation of AGEs, TNFα, and increased catabolism spinal structures; and 3) oral-treatments with a combination of anti-inflammatory and anti-AGE drugs mitigate these diabetes-induced degenerative changes to the spine.
Three age-matched groups of ROP-Os mice were compared: non-diabetic, diabetic (streptozotocin (STZ)-induced), or diabetic mice treated with pentosan-polysulfate (anti-inflammatory) and pyridoxamine (AGE-inhibitor). Mice were euthanized and vertebra-IVD segments were analyzed by μCT, histology and Immunohistochemistry.
Diabetic mice exhibited several pathological changes including loss in IVD height, decreased vertebral bone mass, decreased glycosaminoglycan content and morphologically altered IVDs with focal deposition of tissues highly expressing TNFα, MMP-13 and ADAMTS-5. Accumulation of larger amounts of methylglyoxal suggested that AGE accumulation was associated with these diabetic degenerative changes. However, treatment prevented or reduced these pathological effects on vertebrae and IVD.
This is the first study to demonstrate specific degenerative changes to nucleus pulposus (NP) morphology and their association with AGE accumulation in a diabetic mouse model. Furthermore, this is the first study to demonstrate that oral-treatments can inhibit AGE-induced ROS and inflammation in spinal structures and provide a potential treatment to slow progression of degenerative spine changes in diabetes. Since diabetes, IVD degeneration, and accumulation of AGEs are frequent consequences of aging, early treatments to reduce AGE-induced ROS and Inflammation may have broad public-health implications.
糖尿病和腰痛是使人虚弱的疾病，也是现代的流行病。糖尿病和肥胖症也与椎间盘（IVD）退变和腰痛高度相关。晚期糖基化终产物（AGEs）会增加活性氧（ROS）和炎症，是导致糖尿病早期发生的原因之一。我们假设糖尿病会导致 AGE 在脊柱中积累，并通过增加分解代谢导致相关的脊柱病变。我们提出了一个小鼠模型，表明：1）糖尿病会导致 IVD 和椎骨的结构和组成发生病理性变化；2）糖尿病与 AGEs、TNFα 的积累以及脊柱结构的分解代谢增加有关；3）联合使用抗炎和抗 AGE 药物的口服治疗可减轻这些糖尿病引起的脊柱退行性变化。
比较了三组年龄匹配的 ROP-Os 小鼠：非糖尿病组、糖尿病组（链脲佐菌素（STZ）诱导）或糖尿病组用戊聚糖多硫酸盐（抗炎）和吡哆胺（AGE 抑制剂）治疗。处死小鼠，用μCT、组织学和免疫组织化学分析椎骨-IVD 段。
糖尿病小鼠表现出多种病理变化，包括 IVD 高度丧失、椎骨骨量减少、糖胺聚糖含量减少以及 IVD 形态改变，伴有 TNFα、MMP-13 和 ADAMTS-5 高度表达的组织局灶性沉积。积累了更多的甲基乙二醛表明 AGE 的积累与这些糖尿病退行性变化有关。然而，治疗可预防或减轻这些对椎骨和 IVD 的病理影响。
这是首次在糖尿病小鼠模型中证明了核髓（NP）形态的特定退行性变化及其与 AGE 积累的关系。此外，这也是首次证明口服治疗可以抑制脊柱结构中 AGE 诱导的 ROS 和炎症，并为减缓糖尿病脊柱退行性变的进展提供一种潜在的治疗方法。由于糖尿病、IVD 退变和 AGE 的积累是衰老的常见后果，早期治疗以减少 AGE 诱导的 ROS 和炎症可能具有广泛的公共卫生意义。
