Osteoimmunology of Retarded Bone Regeneration in Periodontitis

牙周炎骨再生迟缓的骨免疫学

基本信息

批准号：
10672563
负责人：
TOSHIHISA KAWAI
金额：
$ 0.64万
依托单位：
NOVA SOUTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10672563
关键词：
Accounting Activated Lymphocyte Adult Affect Age American Bacteria Bone Matrix Bone Regeneration Bone Resorption Bone remodeling CD100 antigen Cell membrane Cells Characteristics Coculture Techniques Coupling Defect Dendritic Cells Development Disease Ensure Event Excision Generations Glycine decarboxylase Goals Histocytochemistry In Vitro Infection Inflammation Inflammatory Injections Integral Membrane Protein Interruption Knockout Mice Ligand Binding Ligands Ligature Lytic Mediating Mediator of activation protein Membrane Messenger RNA Molecular Monoclonal Antibodies Mus NIH 3T3 Cells Osteoblasts Osteoclasts Osteogenesis Pathogenicity Pathologic Periodontitis Phosphorylation Population Porphyromonas gingivalis Production Protein-arginine deiminase Publishing RNA analysis Reporting Role Scientist Signal Transduction Small Interfering RNA Somatomedins Structure-Activity Relationship TNFSF11 gene Testing Time Tooth structure Up-Regulation Vimentin aged alveolar bone base 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 periodontopathogen receptor regenerative therapy release factor response skeletal transcriptome transcriptome sequencing vector

项目摘要

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.

即使在成功进行常规牙周治疗后，骨再生迟缓也是牙周炎的特征。治疗中，牙周骨再生很少发生（如果有的话），而潜在的分子机制骨再生迟缓在很大程度上是未知的，该 RO1 应用建议利用破骨细胞 (OC) 特异性细胞膜受体、破骨细胞刺激物的骨免疫学作用跨膜蛋白 (OCSTAMP) 和树突状细胞特异性跨膜蛋白 (DC-STAMP) 牙周炎中骨再生延迟在破骨细胞骨吸收过程中，成骨细胞（OB）激活。胰岛素样生长因子 (IGF) 等分子充当脱矿骨释放的“偶联”因子基质以确保等量的 OC 吸收的骨被骨的分化和活性所取代 OB. 强有力的证据表明，这种耦合机制在牙周炎中被中断（“解耦合”）。致病性骨吸收超过修复性骨形成，导致骨再生迟缓。我们的初步结果表明，牙龈卟啉单胞菌可能参与延迟骨再生最近的一项研究报道，OC 产生的 Semaphorin4D (Sema4D) 会抑制 IGF 介导的作用。 OB 诱导/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 的作用机制我们初步确定 OCSTAMP 的配体是由什么产生的。激活 OCp，该配体与 OCSTAMP 的结合引发 Sema4D 表达信号。此外，牙周病原体 P. gingivalis 似乎通过以下方式上调 OCp 的 Sema4D 产生：基于这些初步发现和已发表的证据，上调 OCSTAMP 配体的生成。我们发现 OCSTAMP 的配体致病性激活上调 Sema4D 的产生形成 OCp，进而抑制牙周炎中的成骨。为了检验我们的假设，以下两个。提出了具体目标目标 1：阐明配体生成的分子机制。对于 OC-STAMP，目标 2：评估 OC-STAMP 激活对骨再生迟缓的影响结扎附着和牙龈卟啉单胞菌感染联合诱导的牙周炎小鼠模型。这项研究将首次阐明中断新的病理性骨免疫学机制。受牙周炎影响的牙槽骨中的骨形成，因此代表了潜在的范式转变开发新的牙周炎疗法。