Osteoblast Dopamine Receptor Mediates Diabetic Bone Disease

摘要 据估计，美国至少有1亿人患有糖尿病。糖尿病骨病是一种 1型和2型糖尿病的并发症。糖尿病骨骼疾病导致活动能力下降，原因是 骨折风险增加，并有进一步的并发症，最终可能是致命的。低骨密度，即 常用于诊断糖尿病骨疾病与机械损伤的实际相关性不好 在1型和2型糖尿病中观察到的特性。相比之下，糖尿病骨骼中的胶原蛋白被很好地理解为 有低水平的赖氨酸衍生的生物合成交联物，这是身体力量所必需的 结缔组织，包括骨。然而，有关糖尿病患者赖氨酸氧化酶水平及其调节的研究很少。 骨头是存在的。最近对肠源性内分泌因子的兴趣源于肥胖的后果 手术治疗肥胖者，其中许多人还患有糖尿病。葡萄糖促胰岛素多肽 (GIP)是一种肠源性激素，称为胰岛素。除了靶向胰腺β细胞外，GIP还直接 通过GIP受体(GIPR)靶向成骨细胞，刺激骨合成代谢反应。肠子也会分泌 多巴胺进入外周循环，已被假设为抑制GIP的活性，通过 多巴胺受体，也存在于成骨细胞上。在这里，我们将这些发现和我们自己的数据整合到 遵循范式转换的建议。我们的假设是正常的合成代谢刺激骨形成 糖尿病时GIP产生赖氨酸氧化酶的失调是由肠源性多巴胺介导的 成骨细胞多巴胺D2受体(D2R)在1型和2型糖尿病中的表达。我们建议对此进行测试 C57BL6/J条件性成骨细胞特异性D2R基因敲除小鼠(col1-2.3-cre)的假说 与D2rfl/f1小鼠杂交)。小鼠将同时患上1型和2型糖尿病， 分别给予多次小剂量链脲佐菌素注射(1型糖尿病)和高脂饮食(2型糖尿病)。 分析将包括通过qPCR和所有五个赖氨酰氧化酶家族mrna测量骨骼标记物。 结构由µCT、骨强度、骨组织学为生长板结构，以及各种相关血清 记号笔。我们的假设预测成骨细胞D2R基因敲除小鼠将对1型和 与对照组相比，2型糖尿病引起的骨病理改变。这项提议的高潜在影响是 明确确定驱动重要骨骼的意外新陈代谢关系的关键方面 我们认为1型和2型糖尿病的并发症将对 日益重要的公共卫生问题。可交付成果：一种以前未曾探索过的代谢关系 因此，糖尿病患者肠道和骨骼之间的相互作用将得到明确的识别和支持 使单一基因小鼠模型患上2型和1型糖尿病。数据将指向新的可用药 分子靶标。将获得对糖尿病骨骼疾病的新的机械学见解。

Abstract Diabetes is estimated to affect at least 100 million people in the United States. Diabetic bone disease is a complication of both type 1 and type 2 diabetes. Diabetic bone disease results in decreased mobility due to increased fracture risk with further complications that can ultimately be fatal. Low bone mineral density that is often used to diagnose diabetic bone disease does not correlate well with the actual impairment in mechanical properties observed in type 1 and type 2 diabetes. By contrast, collagen in diabetic bone is well understood to have low levels of lysine-derived biosynthetic cross-links which are essential for the physical strength of connective tissues, including bone. However, few studies of levels and regulation of lysyl oxidase in diabetic bone exist. Recent interest in gut-derived endocrine factors has developed from consequences of bariatric surgery to treat obese individuals, many of whom also suffer from diabetes. Glucose insulinotropic polypeptide (GIP) is a gut-derived hormone known as an incretin. In addition to targeting pancreatic β cells, GIP directly target osteoblasts via the GIP receptor (GIPR), stimulating a bone anabolic response. The gut also secretes dopamine into the peripheral circulation that has been hypothesized to inhibit the activity of GIP, mediated by dopamine receptors, also present on osteoblasts. Here we integrate these findings and our own data into the following paradigm-shifting proposal. Our hypothesis is that normal anabolic stimulation of bone formation and lysyl oxidase production by GIP is dysregulated in diabetes by gut-derived dopamine mediated by the osteoblast dopamine D2 receptor (D2R) in both type 1 and type 2 diabetes. We propose to test this hypothesis in male and female C57BL6/J conditional osteoblast-specific D2r gene knockout mice (Col1-2.3-cre cross-bred with D2rfl/fl mice). Mice will be subjected to development of both type 1 and type 2 diabetes by, respectively, multiple low dose streptozotocin injections (type 1 diabetes), and to high fat diet (type 2 diabetes). Analyses will include measures of bone markers by qPCR plus all five lysyl oxidase family mRNAs, bone structure by µCT, bone strength, bone histology for growth plate structure, and a variety of relevant serum markers. Our hypothesis predicts that osteoblast D2r gene knockout mice will be resistant to both type 1 and type 2 diabetes-induced bone pathology, compared to controls. The high potential impact of the proposal is to definitively identify a critical aspect of an unexpected metabolic relationship that drives a significant bone complication of both type 1 and type 2 diabetes that we contend will have translational implications for an increasingly important public health problem. Deliverables: A previously unexplored metabolic relationship between the gut and bone that is dysregulated in diabetes will thus be definitively identified and supported by subjecting a single genetic mouse model to type 2 and type 1 diabetes. Data will point to novel druggable molecular targets. Novel mechanistic insights into diabetic bone disease will be gained.