Osteoimmunology of Retarded Bone Regeneration in Periodontitis

牙周炎骨再生迟缓的骨免疫学

• 批准号: 10449982
• 负责人: TOSHIHISA KAWAI
• 金额: $ 35.74万
• 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 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449982
• 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

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.

骨再生迟缓是牙周炎的特征。即使在成功进行常规牙周治疗后 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) 牙周炎中骨再生迟缓。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”），其中 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 牙周炎。最近的一项研究报道，OC 产生的 Semaphorin4D (Sema4D) 抑制 IGF 介导的 OB 成骨。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 牙周炎的背景尚不清楚。我们初步确定 OCSTAMP 的配体是由 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： 上调 OCSTAMP 配体的产生。根据这些初步调查结果和已发表的证据， 我们假设 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作用。为了验证我们的假设，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小鼠牙周炎模型。 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。