Combined anti-inflammatory and anti-AGE drug treatments have a protective effect on intervertebral discs in mice with diabetes.
Combined anti-inflammatory and anti-AGE drug treatments have a protective effect on intervertebral discs in mice with diabetes.
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DOI：
10.1371/journal.pone.0064302
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Iatridis JC
中科院分区：
文献类型：
--
作者：
Illien-Junger S;Grosjean F;Laudier DM;Vlassara H;Striker GE;Iatridis JC
糖尿病和腰痛是使人衰弱的疾病和现代流行病。糖尿病和肥胖也与椎间盘（IVD）退变和背痛高度相关。晚期糖基化终产物（AGEs）增加活性氧（ROS）和炎症，是糖尿病早期发展的原因之一。我们假设糖尿病导致AGEs在脊柱中的积累，并通过增加catalysts导致相关的脊柱病理学。我们提供了一种小鼠模型，显示：1）糖尿病诱导IVD和椎骨的结构和组成发生病理变化; 2）糖尿病与AGEs、TNFα的蓄积和catastrophic脊柱结构增加相关; 3）抗炎和抗AGE药物联合口服治疗可减轻这些糖尿病诱导的脊柱退行性变化。比较了三组年龄匹配的ROP-Os小鼠：非糖尿病、糖尿病（链脲佐菌素（STZ）诱导）或用戊聚糖多硫酸酯（抗炎）和吡哆胺（AGE抑制剂）治疗的糖尿病小鼠。将小鼠安乐死，并通过μCT、组织学和免疫组织化学分析脊椎IVD节段。糖尿病小鼠表现出多种病理学变化，包括IVD高度降低、椎体骨量减少、糖胺聚糖含量降低和IVD形态学改变，伴有高表达TNFα、MMP-13和ADAMTS-5的组织局灶性沉积。大量丙酮醛的蓄积表明AGE蓄积与这些糖尿病退行性变化相关。然而，治疗预防或减少了对椎骨和IVD的这些病理学影响。这是第一项研究，以证明具体的退行性变化，髓核（NP）形态和他们的关联与AGE积累在糖尿病小鼠模型。此外，这是第一项证明口服治疗可以抑制AGE诱导的ROS和脊柱结构炎症的研究，并提供了一种潜在的治疗方法来减缓糖尿病退行性脊柱变化的进展。由于糖尿病、IVD变性和AGEs积累是衰老的常见后果，因此减少AGEs诱导的ROS和炎症的早期治疗可能具有广泛的公共卫生意义。
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.
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影响因子：
4.9
作者：
Le Maitre, Christine Lyn;Hoyland, Judith Alison;Freemont, Anthony J
通讯作者：
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影响因子：
5.5
作者：
Hoyland, J. A.;Le Maitre, C.;Freemont, A. J.
通讯作者：
Freemont, A. J.