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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：
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
项目类别：
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

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.

骨再生迟缓是牙周炎的特征。即使在常规牙周治疗成功后