Abstract
ObjectiveDiabetes 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.MethodsThree 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.ResultsDiabetic 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.ConclusionThis 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.
Highlights
Low back pain is among the most common conditions requiring medical care with 40.5M patient visits in 2005, enormous annual medical costs ($193.9B and rising) and substantial lost productivity [1,2]
Treatment prevented or reduced these pathological effects on vertebrae and intervertebral disc (IVD). This is the first study to demonstrate specific degenerative changes to nucleus pulposus (NP) morphology and their association with advanced glycation end products (AGEs) accumulation in a diabetic mouse model. 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
Mice that maintained blood glucose levels (.200 mg/dl) for 1 month were randomized to two groups: Diabetic (Db) mice which were maintained without insulin treatment for another 5 months, and treated mice that underwent the same diabetes induction protocol but were given 5 months of treatments including: Pyridoxamine (PYR, an AGE inhibitor), and Pentosan Polysulphate (PPS, a broad acting anti-inflammatory)
Summary
Low back pain is among the most common conditions requiring medical care with 40.5M patient visits in 2005, enormous annual medical costs ($193.9B and rising) and substantial lost productivity [1,2]. Low back pain is often related to intervertebral disc (IVD) pathologies including degeneration [3,4]. The causes for IVD degeneration are multifactorial and risk factors include heritability, rapid increase in weight, obesity and physical activity levels [4,5,6]. Juvenile disc degeneration was strongly associated with obesity, low back pain, increased low back pain intensity, and diminished physical and social functioning with a significant association of elevated body mass index with severity of disc degeneration [6,7]. Diabetes Mellitus (DM) is a systemic disease reaching epidemic proportions on world-wide basis, and DM causes degenerative changes of most of the body organ systems [8] including the nervous, cardiovascular, kidney, and the musculoskeletal systems [9,10,11,12,13]. The WHO reports that more than 346 million people worldwide have diabetes
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