ROLE OF OSTEOCLAST PRECURSORS IN PERIODONTAL BONE LOSS

破骨细胞前体在牙周骨丢失中的作用

• 批准号: 9381236
• 负责人: Ping Zhang
• 金额: $ 35.27万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-17 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381236
• 关键词: Aging; Alpha Cell; Alveolar Bone Loss; Binding; Bone Marrow; Bone Resorption; CD4 Positive T Lymphocytes; CSF1R gene; Cell Cycle Arrest; Cell Proliferation; Cell physiology; Cells; Characteristics; Chronic; Development; Disease; Down-Regulation; Exposure to; Frequencies; Grant; Hematopoietic; Immune response; Immunosuppression; In Vitro; Infection; Inflammation; Inflammatory; Interleukin-1; Knowledge; Ligands; Macrophage Colony-Stimulating Factor Receptor; Maintenance; Mediating; Modeling; Molecular; Mus; Nature; Osteoclasts; Pathogenesis; Pathogenicity; Pathologic; Periodontal Diseases; Periodontal Infection; Periodontitis; Phenotype; Play; Porphyromonas gingivalis; Predisposition; Prevention; Process; Publishing; Receptor Cell; Receptor Signaling; Regulation; Research; Research Personnel; Role; Site; Spleen; TLR2 gene; TNF gene; Testing; Therapeutic Intervention; Time; Toll-like receptors; Virulence Factors; Work; alveolar bone; base; bone; bone loss; c-fms Proto-Oncogenes; cytokine; granulocyte; immunoregulation; in vivo; inflammatory bone loss; insight; macrophage; monocyte; mouse model; novel; novel diagnostics; novel therapeutics; pathogen; pathogenic bacteria; precursor cell; predictive modeling; receptor; response; targeted treatment

Project Summary Excessive activity of osteoclasts (OC), the body's sole bone resorbing cells, is a major characteristic of pathogenic bone loss in periodontitis. Although a great deal is known about the process of OC differentiation, the identity of OC precursors (OCP) in vivo, and their role in periodontitis remain scarce, especially in aging where the extent of bone loss is increased. Recent studies have identified a cell cycle-arrested quiescent OCP present in very low numbers. These cells are receptor activator of NF-κB (RANK)-positive and express colony- stimulating factor-1 receptor (c-fms) at various levels, but scarcely express monocyte/macrophage/ granulocyte markers. Using in vivo mouse models, we have shown that infection with the periodontal-associated pathogen Porphyromonas gingivalis (Pg) induces the expansion of an earlier stage c-fms+RANK- OCP (eOCP) and the more advanced stage RANK+ OCP (rOCP) in bone marrow and spleen. In addition, eOCP and rOCP potently suppress CD4+ T cell proliferation in vitro, highlighting an important role of OCP in immune regulation. Moreover, compared to young mice, old mice show increased periodontal bone loss, as well as increased OCP frequency and osteoclastogenic potential, suggesting that increased OCP pool underlies host susceptibility to periodontal bone loss in aging. Based on our preliminary studies and published work, we hypothesize that Pg infection results in the expansion of OCP that can be shunted toward OC formation and bone loss at the infection/inflammation sites, while at the same time dampen host immune responses, which is beneficial for the persistence of infection and maintenance of chronic inflammation. We will test our hypothesis by pursuing two specific aims: 1) Delineate the regulation of OCP following Pg infection; 2) Determine the effect of OCP on host immune responses and bone loss in vivo to Pg infection. Our proposed studies will provide novel and significant insight into the pathogenesis of Pg infection and periodontitis leading to the potential development of targeted therapeutics for inflammatory bone loss diseases.

项目摘要 破骨细胞（OC）的过度活性（OC）是人体的唯一骨骼吸收细胞，是一个主要特征 牙周炎的致病性骨质流失。尽管关于OC差异化过程有很多了解，但 OC前体的身份（OCP）在体内及其在牙周炎中的作用仍然很少，尤其是在衰老中 骨质流失程度增加的地方。最近的研究已经确定了细胞周期戒断的OCP 数量很少。这些细胞是NF-κB（秩）阳性和表达菌落的受体激活剂 在各种水平上刺激因子1受体（C-FMS），但几乎没有表达单核细胞/巨噬细胞/粒细胞 标记。使用体内小鼠模型，我们表明感染与牙周相关的病原体 卟啉单胞菌（PG）诱导了早期的C-FMS+等级OCP（EOCP）和 骨髓和脾脏中更高级的阶段排名+ OCP（ROCP）。另外，EOCP和ROCP可能 在体外抑制CD4+ T细胞增殖，突出了OCP在免疫调节中的重要作用。 此外，与年轻小鼠相比，老鼠显示牙周骨质流失增加，OCP增加 频率和破骨细胞生成潜力，表明增加的OCP池是宿主易感性的基础 衰老中的牙周骨质流失。根据我们的初步研究和发表的工作，我们假设PG 感染导致OCP的扩展，可以分流向OC形成和骨质流失。 感染/炎症部位，同时抑制宿主免疫反应，这对 感染的持续性和慢性感染的维持。我们将通过追求两个来检验我们的假设 具体目的：1）描述PG感染后OCP的调节； 2）确定OCP对宿主的影响 体内对PG感染的免疫反应和骨质流失。我们提出的研究将提供新颖， 对PG感染和牙周炎的发病机理的重大见解，导致潜在的发展 针对炎症性骨质流失疾病的靶向疗法。