Impact of acid ceramidase activity on MIF-mediated migration of circulating osteoclast precursors to periodontal bone lesions in relation to aging

酸性神经酰胺酶活性对 MIF 介导的循环破骨细胞前体向与衰老相关的牙周骨病变迁移的影响

• 批准号: 10199553
• 负责人: Alexandru Movila
• 金额: $ 6.35万
• 依托单位: NOVA SOUTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10199553
• 关键词: Affect; Age; Aging; Alveolar Bone Loss; Binding; Blood; Bone Resorption; CXCR4 Receptors; Ceramides; Chemotaxis; Development; Elderly; Epithelial Cells; Fibroblasts; Gingiva; Human; In Vitro; Incidence; Inflammatory; Lead; Lesion; Lipids; Mediating; Migration Inhibitory Factor; Mus; Oral; Osteoclasts; Pathogenesis; Pathogenicity; Penetration; Periodontal Diseases; Periodontitis; Periodontium; Population; Porphyromonas gingivalis; Production; Publications; Reporting; Role; Site; Societies; Source; TNFSF11 gene; Testing; Therapeutic; Tissues; Virulent; age effect; age related; aged; aging population; bone; bone loss; design; dihydroceramide; fibroblast migration inhibitory factor; galactosylgalactosylglucosylceramidase; in vivo; inflammatory bone resorption; migration; novel; novel diagnostics; osteoclastogenesis; pathogen; prevent; response; tool

ABSTRACT There is a critical need for new strategies to prevent and/or treat periodontal bone loss in the aging society of the U.S. However, the underlying mechanisms for age-dependently elevated incidence and pathogenic manifestations of periodontitis, especially bone resorption, remain elusive. This study will investigate the novel host-bacterial interaction of which pathogenesis only emerges with aging in periodontitis. Our earlier studies demonstrated that that a novel virulent lipid, phosphoglycerol dihydroceramide (PGDHC), produced by the keystone pathogen Porphyromonas gingivalis upregulates RANKL-induced osteoclastogenesis in vitro and in vivo, and that locally produced macrophage migration inhibitory factor (MIF) in inflammatory bone resorption lesion induces chemotaxis of blood circulating osteoclast precursors to bone resorption site via binding to its cognate receptor CXCR4. Our preliminary in vitro results showed that, PGDHC-induced MIF-production from fibroblasts, a primary cellular source of MIF in periodontal lesions, is significantly upregulated by those isolated from old mice, compared to young mice, while bacterial LPS did not show any age-dependent change in production of MIF from fibroblasts. Other preliminary results demonstrated that host acid ceramidase (aCDase) downregulates PGDHC-elicited osteoclastogenesis and that aCDase expression is significantly diminished in healthy gingival tissue of aged mice compared to young mice. In relation to those results, our recent publication reported that P. gingivalis downregulates expression of aCDase expression from host epithelial cells in vitro. Collectively, it is highly plausible that host derived aCDase has a protective role against the virulent lipid PGDHC, and age-dependently diminished aCDase activity may leads to breach of active PGDHC to periodontal tissue. Thus, we hypothesized that age-dependently altered aCDase activity in periodontal lesions may be responsible for protecting host from PGDHC lipid produced by P. gingivalis. The Aim 1 is designed to test protective the role of age-dependently altered aCDase activity against PGDHC-mediated pathogenesis, especially the local production of MIF. In Aim 2, effects of age-dependently increased tissue penetration of active PGDHC on chemotaxis of blood circulating osteoclast precursors to bone resorption site will be examined in vitro as well as in periodontatis induced in young and aged mice. Completion of these studies is anticipated to cause the paradigm-shit in the study of host-oral bacterial interaction in age-associated periodontitis and help development of novel diagnostic tools and therapeutic regimes for age-associated periodontitis.

抽象的 迫切需要采取新策略来预防和/或治疗衰老社会的牙周骨质流失 但是，美国，与年龄依赖性升高的发病率和致病性的基本机制 牙周炎的表现，尤其是骨吸收，仍然难以捉摸。这项研究将调查 新型的宿主 - 细菌相互作用，其发病机理仅随牙周炎衰老而出现。我们的 较早的研究表明，一种新型的毒脂质磷酸甘油二氢可酰胺（PGDHC）， 由Keystone病原体卟啉单胞菌产生 体外和体内，以及局部产生的巨噬细胞迁移抑制因子（MIF）在炎症骨中 吸收病变通过结合诱导血液循环的骨输血位点的循环骨前体的趋化性 与其同源受体CXCR4。我们的初步体外结果表明，PGDHC诱导的MIF生产 从成纤维细胞中，牙周病变中MIF的主要细胞来源显着上调 与年轻小鼠相比，与老鼠分离 在成纤维细胞生产MIF中。其他初步结果表明宿主酸性神经酶（ACDASE） 下调pGDHC诱导的破骨细胞生成，而ACDase表达显着降低 与年轻小鼠相比，在健康小鼠的健康牙龈组织中。关于这些结果，我们最近 出版报道，牙龈疟原虫下调了宿主上皮细胞的ACDase表达的表达 体外。总体而言，高度合理的是，宿主衍生的ACDase具有针对毒性脂质的保护作用 PGD​​HC和年龄依赖性降低的ACDase活性可能导致侵犯活性PGDHC牙周 组织。因此，我们假设牙周病变中与年龄依赖性的ACDase活性改变可能是 负责保护宿主免受牙龈疟原虫产生的PGDHC脂质。目标1旨在测试 保护年龄依赖性改变的ACDase活性对PGDHC介导的发病机理的作用， 特别是MIF的本地生产。在AIM 2中，活跃的组织渗透的年龄依赖性增加的组织渗透 将在体外检查对骨吸收部位的血液循环破骨细胞前体的PGDHC 以及在年轻小鼠和老年小鼠中诱导的牙周化中。这些研究的完成预计会导致 在与年龄相关牙周炎中宿主的细菌相互作用的研究中，范式刺激 开发与年龄相关牙周炎的新型诊断工具和治疗方案的开发。