Osteoimmunology of Retarded Bone Regeneration in Periodontitis

牙周炎骨再生迟缓的骨免疫学

• 批准号: 10885237
• 负责人: TOSHIHISA KAWAI
• 金额: $ 1.04万
• 依托单位: NOVA SOUTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10885237
• 关键词: Accounting; Activated Lymphocyte; Adult; Affect; Age; Alveolar Bone Loss; American; Autoantibodies; Bacteria; Bone Matrix; Bone Regeneration; Bone Resorption; Bone remodeling; CD100 antigen; Cell membrane; Cells; Characteristics; Coculture Techniques; Coupling; Defect; Dendritic Cells; Development; Disease; Event; Excision; Generations; Goals; Histocytochemistry; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Injections; Integral Membrane Protein; Interruption; Knockout Mice; Ligand Binding; Ligands; Ligature; Lytic; Mediating; Membrane; Messenger RNA; Molecular; Monoclonal Antibodies; Mus; NIH 3T3 Cells; Osteoblasts; Osteoclasts; Osteogenesis; Pathogenicity; Pathologic; Periodontitis; Persuasive Communication; Phenotype; Phosphorylation; Population; Porphyromonas gingivalis; Production; Protein-arginine deiminase; Proteins; Publishing; Reporting; Role; Scientist; Signal Transduction; Site; Small Interfering RNA; Somatomedins; Structure-Activity Relationship; TNFSF11 gene; Testing; Time; Tooth structure; Up-Regulation; Vimentin; aged; alveolar bone; bone; bone loss; citrullinated protein; demineralization; functional genomics; gain of function; in vivo; in vivo imaging; inhibitor; insight; loss of function; monocyte; mouse model; multimodality; new therapeutic target; novel; osteoclastogenesis; osteogenic; osteoimmunology; overexpression; pathogen; periodontopathogen; protein activation; receptor; regenerative therapy; release factor; response; skeletal; transcriptome; transcriptome sequencing; vector

Retarded bone regeneration is characteristic to periodontitis. Even after successful conventional periodontal treatment, periodontal bone regeneration rarely, if ever, occurs, while molecular mechanism underlying retarded bone regeneration is largely unknown. This RO1 application proposes to exploit the osteoimmunological roles of osteoclast (OC)-specific cell membrane receptor, Osteoclast Stimulatory Transmembrane Protein (OCSTAMP) and Dendritic Cell-Specific Transmembrane Protein (DC-STAMP) in retarded bone regeneration in periodontitis. During osteoclastic bone resorption, osteoblast (OB)-activation molecules, such as insulin-like growth factor (IGF), act as “coupling” factors released from demineralized bone matrix to ensure that the same amount of bone resorbed by OC is replaced by differentiation and activity of OB. Strong evidence suggests that this coupling mechanism is interrupted (‘uncoupled’) in periodontitis where pathogenic bone resorption exceeds reparative bone formation, resulting in retardation of bone regeneration. Our preliminary results showed that P. gingivalis may be engaged in retarded bone regeneration in periodontitis. A recent study reported that Semaphorin4D (Sema4D) produced by OC inhibits IGF-mediated osteogenesis by OB. The upstream molecular event(s) that induce(s)/upregulate(s) Sema4D expression by RANKL-activated osteoclast precursors (OCp), as well as the mechanism of Sema4D action on OB in the context of periodontitis, are unknown. We preliminary identify the ligand for OCSTAMP is produced by activated OCp, and the binding of this ligand with OCSTAMP elicits signals for Sema4D-expression. Furthermore, periodontal pathogen, P. gingivalis, appears to upregulate the Sema4D production from OCp by upregulating the generation of OCSTAMP ligand. Based on these preliminary findings and published evidence, we hypothesized that pathogenic activation of OCSTAMP by its ligand upregulate the production of Sema4D form OCp which, in turn, inhibits osteogenesis in periodontitis. To test our hypothesis, the following two Specific Aims are proposed. Aim 1: To elucidate the molecular mechanism underlying the generation of ligand for OC-STAMP, Aim 2: To assess the impact of OC-STAMP-activation on retarded bone regeneration in a mouse model of periodontitis induced by the combination of ligature attachment and P. gingivalis infection. This study will, for the first time, elucidate the pathologic osteoimmunological mechanism that interrupts new bone formation in alveolar bone affected by periodontitis, thus, representing a potential paradigm shift in the development of novel periodontitis therapies.

延迟的骨再生是牙周炎的特征。即使在成功的常规牙周炎之后 治疗，牙周骨再生很少发生，如果发生的话， 延迟的骨骼再生在很大程度上未知。此RO1申请提案以利用 破骨细胞（OC）特异性细胞膜受体的破骨免疫学作用，骨刺激性刺激性 跨膜蛋白（Ocstamp）和树突状细胞特异性跨膜蛋白（DC-Stamp） 牙周炎的骨骼再生。在整骨骨溶解期间，成骨细胞（OB）激活 分子，例如胰岛素样生长因子（IGF），充当了从解矿化骨骼释放的“耦合”因子 矩阵以确保OC吸收相同数量的骨头被分化和活性所取代 ob。有力的证据表明，这种耦合机制在牙周炎中被中断（“未偶联”），其中 致病性骨骼分辨率超过修复性骨形成，导致骨再生的迟缓。 我们的初步结果表明，牙龈疟原虫可能参与智障的骨骼再生 牙周炎。最近的一项研究报告说，OC产生的Semaphorin4d（SemA4D）抑制了IGF介导的 OB的成骨。通过影响（S）/上调SEMA4D表达的上游分子事件 RANKL激活的破骨细胞前体（OCP）以及SEMA4D对OB的机制 牙周炎的背景是未知的。我们初步识别Ocstamp的配体是由 活化的OCP，该配体与Ocstamp的结合引起了SEMA4D表达的信号。 此外，牙周病原体（牙龈疟原虫）似乎通过OCP更新SEMA4D生产 上调Ocstamp配体的产生。基于这些初步发现和已发表的证据， 我们假设Ocstamp通过配体的致病激活上调了Sema4d的产生 OCP形式又抑制了牙周炎的成骨。为了检验我们的假设，以下两个 提出了具体目标。目标1：阐明配体产生的分子机制 对于OC-Stamp，目标2：评估OC stamp激活对智障骨再生的影响 牙周炎的小鼠模型是由绑扎附着和牙龈疟原虫感染的组合引起的。 这项研究将首次阐明中断新的病理骨气免疫机制 因此，牙槽骨形成受牙周炎影响 新型牙周炎治疗的发展。