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.

摘要