Alveolar Bone Regeneration in Diabetic Periodontitis

糖尿病牙周炎的牙槽骨再生

• 批准号: 10058838
• 负责人: JAKE JINKUN CHEN
• 金额: $ 39.19万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-12 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058838
• 关键词: Adult; Affinity; Agonist; Alveolar Bone Loss; American; Anti-Inflammatory Agents; Antidiabetic Drugs; Binding; Blood; Blood Glucose; Bone Diseases; Bone Formation Inhibition; Bone Regeneration; Bone Resorption; Cell Differentiation process; Cells; Cellular Metabolic Process; Chemicals; Defect; Diabetes Mellitus; Diabetic mouse; Disadvantaged; Disease; Dose; Frequencies; Gene Expression; Genes; Glucose Intolerance; Goals; Hyperglycemia; Impairment; Infiltration; Inflammation; Inflammatory; Injections; Insulin Resistance; Investigation; Knock-out; Knockout Mice; Label; Literature; Longevity; Measurement; Measures; Mediator of activation protein; Mesenchymal Stem Cells; Metabolic; Methods; Modeling; Molecular; Natural regeneration; Nature; Non-Insulin-Dependent Diabetes Mellitus; Oral; Osteoblasts; Osteoclasts; Osteogenesis; Pathology; Pattern; Periodontal Diseases; Periodontitis; Phenotype; Population; Property; Proteins; Refractory; Role; Sampling; Severities; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Specificity; Stromal Cell-Derived Factor 1; Therapeutic; Therapeutic Agents; Therapeutic Effect; Time; Tooth structure; Translational Research; adipokines; adiponectin; aged; alveolar bone; base; bone; bone cell; bone healing; clinical application; diabetic; diabetic patient; drug development; fluorexon; healing; immunoreaction; insight; insulin sensitizing drugs; microCT; migration; mouse model; non-diabetic; novel; novel therapeutics; osteoblast differentiation; osteoclastogenesis; osteogenic; preservation; receptor; recruit; repaired; small molecule; stem cell migration; stem cells; wound

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.

超过 47% 的 30 岁及以上美国成年人患有牙周炎。此外，牙周炎的发病率是 与非糖尿病患者一样，2 型糖尿病 (T2D) 在糖尿病患者中也很常见，目前有 4000 万美国人患有 2 型糖尿病 (T2D)。 T2D 相关的牙周炎很严重，并且在许多情况下，由于牙齿结构的改变，目前的治疗方法难以治愈。 以及高血糖条件下骨细胞的异常功能。因此，开发一种有效的方法 恢复和再生丢失的牙槽骨以保留糖尿病患者的天然牙齿至关重要。 脂联素是一种脂肪因子，具有抗炎和抗糖尿病特性。我们发现脂联素 抑制破骨细胞的分化和活性，显着减少牙槽骨丢失。同时 同时，它促进成骨细胞微环境和间充质干细胞迁移，增强骨缺损愈合。 然而，基于脂联素蛋白的疗法有限制其临床应用的缺点，包括 不良免疫反应以及需要持续静脉注射高剂量才能达到治疗效果。一个 脂联素受体激动剂 AdipoRon (APR) 最近被鉴定出来（Nature 503:493-9, 2013），它可以 口服可改善胰岛素抵抗和葡萄糖耐受不良，并延长缩短的时间 糖尿病小鼠的寿命。我们的初步研究表明 APR 上调表达和活性 脂联素受体对骨细胞代谢发挥有利作用。我们的目的是使用APR，一个小的 分子化合物，作为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不平衡，逆转病理并 促进丢失牙槽骨的再生，并保留天然牙齿。在目标 1 中，我们将 首先确定 APR 与骨细胞中脂联素受体结合的亲和力和功效，启动 下游信号介质表达，并增强骨形成。为了验证特异性和 这种新型外源激动剂和内源受体之间相互作用的亲和力，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“活动障碍”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。我们将使用一个 脂联素敲除小鼠系以确定 APR 是否可以有效替代脂联素促进 必要的微环境并部署足够的骨形成细胞来再生受损的牙槽骨 在牙周炎中。在目标 3 中，我们将在糖尿病小鼠模型中生成实验性牙周炎，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。这项转化研究将得出一部小说的初步特征 具有治疗糖尿病牙周病潜力并提供基线信息的治疗剂 用于治疗牙周炎和其他与糖尿病相关的骨病的药物开发。

项目成果

Identification and characterization of a novel adiponectin receptor agonist adipo anti-inflammation agonist and its anti-inflammatory effects in vitro and in vivo.

• DOI: 10.1111/bph.15277
• 发表时间: 2021-01
• 期刊: British journal of pharmacology
• 影响因子: 7.3
• 作者: Qiu W;Wu H;Hu Z;Wu X;Tu M;Fang F;Zhu X;Liu Y;Lian J;Valverde P;Van Dyke T;Steffensen B;Dong LQ;Tu Q;Zhou X;Chen J
• 通讯作者: Chen J

Osteogenic effects of microRNA-335-5p/lipidoid nanoparticles coated on titanium surface.

• DOI: 10.1016/j.archoralbio.2021.105207
• 发表时间: 2021-09
• 期刊: Archives of oral biology
• 影响因子: 3
• 作者: Wang Q;Wang X;Valverde P;Murray D;Dard MM;Van Dyke T;Xu Q;Xu X;Karimbux N;Tu Q;Chen J
• 通讯作者: Chen J

AdipoRon promotes diabetic fracture repair through endochondral ossification-based bone repair by enhancing survival and differentiation of chondrocytes.

• DOI: 10.1016/j.yexcr.2019.111757
• 发表时间: 2020-02-15
• 期刊: Experimental cell research
• 影响因子: 3.7
• 作者: Wang Z;Tang J;Li Y;Wang Y;Guo Y;Tu Q;Chen J;Wang C
• 通讯作者: Wang C

Overexpression of MiR-335-5p Promotes Bone Formation and Regeneration in Mice.

• DOI: 10.1002/jbmr.3230
• 发表时间: 2017-12
• 期刊: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
• 作者: Zhang L;Tang Y;Zhu X;Tu T;Sui L;Han Q;Yu L;Meng S;Zheng L;Valverde P;Tang J;Murray D;Zhou X;Drissi H;Dard MM;Tu Q;Chen J
• 通讯作者: Chen J

Epigenetic Modulation in Periodontitis: Interaction of Adiponectin and JMJD3-IRF4 Axis in Macrophages.

• DOI: 10.1002/jcp.25201
• 发表时间: 2016-05
• 期刊: Journal of cellular physiology
• 影响因子: 5.6
• 作者: Xuan D;Han Q;Tu Q;Zhang L;Yu L;Murry D;Tu T;Tang Y;Lian JB;Stein GS;Valverde P;Zhang J;Chen J
• 通讯作者: Chen J