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岁及以上的美国成年人患有牙周炎。此外，牙周炎是 糖尿病患者和非糖尿病患者一样普遍，2型糖尿病（T2 D）目前困扰着4000万美国人。 T2 D相关的牙周炎是严重的，并且在许多情况下，由于改变的牙周膜，对当前的治疗是难治的。 以及高血糖状态下骨细胞的异常功能。因此，开发一种有效的方法， 恢复和再生失去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的作用。我们发现脂联素 抑制破骨细胞的分化和活性，显著减少牙槽骨丢失。在同一 同时，促进成骨细胞龛和间充质干细胞迁移，促进骨缺损愈合。 然而，基于脂联素蛋白的治疗存在限制其临床应用的缺点，包括 不良免疫反应和需要恒定IV注射高剂量以达到治疗效果。一个 最近鉴定了脂联素受体激动剂AdipoRon（APR）（Nature 503：493-9，2013），其可以是 口服给药以改善胰岛素抵抗和葡萄糖耐受不良，并延长缩短的 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，作为一种新的治疗剂，有效地治疗糖尿病牙周炎。我们 中心假设是，除了全身控制高血糖和炎症，APR直接 触发分子信号，纠正骨吸收和形成的不平衡，逆转病理， 促进失去的牙槽骨再生，并使天然牙齿得以保留。在目标1中， 首先确定APR与骨细胞中脂联素受体结合的亲和力和效力， 下游信号介质表达和骨形成的增强。验证专属性， 为了确定这种新型外源性激动剂与内源性受体之间相互作用的亲和力，我们将使用受体 把老鼠打晕在目标2中，我们将描述APR在改善和纠正糖尿病“运动病”中的作用- 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 脂联素敲除小鼠系，以确定APR是否可以有效地替代脂联素促进脂联素的表达。 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产生实验性牙周炎，以进一步 确定APR在降低高血糖和炎症方面的总体效果以及其合成代谢作用 用于牙周骨再生。这种翻译研究将产生一部小说的初步特征 具有治疗糖尿病牙周病的强大潜力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。

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