Alveolar Bone Regeneration in Diabetic Periodontitis

超过47%的30岁及以上的美国成年人患有牙周炎。此外，牙周炎的发病率是 在糖尿病患者和非糖尿病患者中普遍存在，2型糖尿病(T2D)目前正困扰着4000万美国人。 T2D相关性牙周炎是严重的，在许多情况下，由于牙周改变而对当前的治疗无效 以及骨细胞在高血糖条件下的异常功能。因此，开发一种有效的方法来 修复和再生丢失的牙槽骨以保留糖尿病患者的天然牙齿是至关重要的。 脂联素是一种脂肪因子，具有抗炎和抗糖尿病的特性。我们发现脂联素 抑制破骨细胞分化和活性，显著减少牙槽骨丢失。同时 时间长，促进成骨细胞巢和间充质干细胞迁移，促进骨缺损愈合。 然而，以脂联素蛋白为基础的治疗有限制其临床应用的缺点，包括 免疫反应不良和需要持续静脉注射大剂量才能达到治疗效果。一个 脂联素受体激动剂AdipoRon(APR)是最近发现的(自然503：493-9,2013)，它可以 口服改善胰岛素抵抗和糖耐量异常，延长缩短的 糖尿病小鼠的寿命。我们的初步研究表明，APR上调了血管内皮细胞的表达和活性 脂联素受体对骨细胞代谢具有良好的作用。我们的目的是使用APR，一个小的 分子化合物，作为一种有效治疗糖尿病牙周炎的新型治疗剂。我们的 中心假设是，除了系统地控制高血糖和炎症外，APR还直接 触发分子信号，纠正骨吸收和形成的失衡，逆转病理和 促进丢失的牙槽骨再生，保留天然牙齿。在目标1中，我们将 首次确定APR与骨细胞中脂联素受体结合的亲和力和有效性，启动 下游信号介体表达，促进骨形成。以验证其特异性和 这种新型外源性激动剂与内源性受体相互作用的亲和力，我们将使用受体 消灭老鼠。在目标2中，我们将描述APR在改善和纠正糖尿病‘运动病变’方面的作用- 其中细胞分化、募集和迁移在糖尿病中严重受损。我们将使用 脂联素敲除小鼠品系确定APR能否有效替代脂联素在促进 必要的微环境和部署足够的骨形成细胞来再生受损的牙槽骨 牙周炎。在目标3中，我们将在糖尿病小鼠模型中建立实验性牙周炎，以进一步 确定APR在降低高血糖和炎症方面的总体效果及其合成代谢作用 用于牙周骨再生。这项翻译研究将产生一部小说的初步特征 具有很大潜力治疗糖尿病牙周疾病的治疗剂，并提供基线信息 用于治疗牙周炎和其他与糖尿病相关的骨骼疾病的药物开发。

Over 47% of American adults aged 30 and over have periodontitis. Further, periodontitis is twice as prevalent in diabetics as in non-diabetics, and type 2 diabetes (T2D) currently afflicts 40 million Americans. T2D-associated periodontitis is severe and, in many cases, refractory to current treatments due to the altered and aberrant functions of bone cells in hyperglycemic conditions. Therefore, developing an effective method to restore and regenerate lost alveolar bone to reserve the natural teeth in diabetics is critically important. Adiponectin, an adipokine, has anti-inflammatory and anti-diabetic properties. We have found that adiponectin inhibits differentiation and activity of osteoclasts and significantly decreases alveolar bone loss. At the same time, it promotes the osteoblast niche and mesenchymal stem cell migration, and enhances bone defect healing. However, adiponectin protein-based therapy has disadvantages that limit its clinical application, including adverse immunoreactions and the need for constant IV injection of high doses for therapeutic effect. An adiponectin receptor agonist, AdipoRon (APR) was recently identified (Nature 503:493-9, 2013), which can be orally administrated to ameliorate insulin resistance and glucose intolerance, and prolong the shortened lifespan of diabetic mice. Our preliminary studies indicate that APR upregulates expression and activity of adiponectin receptors exerting favorable effects on bone cell metabolism. Our purpose is to use APR, a small molecule chemical compound, as a novel therapeutic agent to effectively treat diabetic periodontitis. Our central hypothesis is that, in addition to systemically controlling hyperglycemia and inflammation, APR directly triggers molecular signals that correct the imbalance of bone resorption and formation, reversing pathology and promoting regeneration of lost alveolar bone, and allowing the natural teeth to be reserved. In Aim 1 we will first determine the affinity and efficacy of APR binding to adiponectin receptors in bone cells, initiation of downstream signal mediator expression, and enhancement of bone formation. To verify the specificity and affinity of the interaction between this novel exogenous agonist and endogenous receptor, we will use receptor knock out mice. In Aim 2 we will delineate the APR effect in ameliorating and correcting diabetic 'mobilopathy' - in which cell differentiation, recruitment and migration are seriously impaired in diabetes. We will use an adiponectin knock out mouse line to determine if APR can effectively surrogate adiponectin in promoting the necessary microenvironment and deploying sufficient bone forming cells to regenerate alveolar bone damaged in periodontitis. In Aim 3 we will generate experimental periodontitis in a mouse model of diabetes to further determine the overall effects of APR in reducing hyperglycemia and inflammation as well as its anabolic effect for periodontal bone regeneration. This translational research will yield initial characterization of a novel therapeutic agent with strong potential for treating diabetic periodontal disease and provide baseline information for drug development for treating periodontitis and other bone diseases associated with diabetes.