Role of pro-inflammatory cytokines in drug induced osteonecrosis of the jaw

促炎细胞因子在药物引起的颌骨坏死中的作用

• 批准号: 9193081
• 负责人: Drake Winslow Williams
• 金额: $ 4.98万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9193081
• 关键词: Address; Adverse effects; Award; Biological Assay; Biology; Biopsy; Blood; Bone Diseases; Bone Resorption; Bone necrosis; Cancer Patient; Cells; Clinical; Collagen; Collagen Type I; Complex; Data; Dental; Development; Disease model; Disseminated Malignant Neoplasm; Enzyme-Linked Immunosorbent Assay; Etiology; Extracellular Matrix Proteins; Family; Fibroblasts; Functional disorder; Future; Genes; Gingiva; Goals; Grant; Immature Bone; Impairment; In Vitro; Incidence; Inflammatory; Interleukin-17; Interleukins; Jaw; Knockout Mice; Knowledge; Laboratories; Lesion; Ligands; Luciferases; Malignant Bone Neoplasm; Mediating; Mediator of activation protein; Metastatic Neoplasm to the Bone; Microarray Analysis; Modality; Modeling; Molecular; Mus; Necrosis; Oral; Oral cavity; Oral mucous membrane structure; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Pain; Patients; Pharmaceutical Preparations; Phosphorylation; Play; Proteins; Public Health; Recording of previous events; Reporter; Reporting; Research; Research Personnel; Risk Factors; Role; Sampling; Serum; Signal Pathway; Signal Transduction; Staining method; Stains; Suggestion; Testing; Therapeutic; Time; Tissue Sample; Tissues; Tooth Extraction; Wound Healing; X-Ray Computed Tomography; base; bisphosphonate; bone; career; chromatin immunoprecipitation; cytokine; diagnostic biomarker; experience; healing; high risk; in vivo; insight; knock-down; mineralization; mouse model; neutralizing antibody; oral tissue; pleiotropism; promoter; public health relevance; receptor; secretory protein; sound; therapeutic biomarker

 DESCRIPTION (provided by applicant): Bisphosphonates (BP), a class of anti-resorptive drugs, have a long history of being prescribed to treat bone disorders like osteoporosis and bone metastases in cancer patients. A side effect of anti-resorptive drugs like BPs is that long-term users are at a higher risk of developing BRONJ, which is clinically defined as exposed necrotic bone and unclosed overlaying oral mucosa for at least 8 weeks. The pathophysiology of BRONJ is highly debated most likely due to the pleiotropic effects of BPs. Recently, we have demonstrated that mice with dysfunctional osteoclasts due to BP administration manifest ONJ-like lesions about 30% of the time following dental extraction. While many groups in the field are working to understand how osteoclast dysfunction leads to BRONJ, we have revealed that diminished osteoclast function is required, but not sufficient to induce BRONJ. In order to understand what other factors are involved in BRONJ development, we have identified potential genes involved, specifically IL-36, by performing microarray analysis on biopsied tissues. We have validated the results of this assay both in vitro and in vivo, suggesting that induction of IL 36 by BP leads to suppression of extracellular matrix proteins (i.e. collagen precursors), which are required for re-epithelialization during wound healing, and this suppression may be an etiological factor in BRONJ development. The long- term goal of our research is to understand the molecular mechanisms that give rise to BRONJ and use this disease model to better understand osteomucosal wound healing. In the current study, I propose a hypothesis that IL-36 is a critical cytokine involved in ONJ development and that the IL-36 signaling pathway inhibits bone formation and wound healing via NFĸB and its downstream mediators. Based on our preliminary data, I aim to: 1) Determine the mechanism by which IL-36 inhibits collagen expression; 2) Investigate the direct effects of IL- 36 signaling in vivo; and 3) Investigate IL-36 expression as a risk factor for BRONJ induction. The issue of BRONJ cannot be resolved by reducing or eliminating treatment as the underlying conditions (e.g. osteoporosis, metastatic cancer) are more severe and must be addressed. Thus, determining why BRONJ occurs, how to predict its occurrence, and establishing therapeutic treatments is critical for the patients who will experience this condition. Successful completion of the current project will address all of these issues and make significant contributions to understanding the etiopathogenesis of this painful malady. This award will prepare the trainee for an academic career as an independent researcher in wound healing and bone biology.

 描述（由申请人提供）：双膦酸盐（BP）是一类抗骨吸收药物，长期用于治疗癌症患者的骨质疏松症和骨转移等骨疾病。抗再吸收药物如BP的副作用是长期使用者患BRONJ的风险更高，BRONJ在临床上定义为暴露的坏死骨和未闭合的覆盖口腔粘膜至少8周。BRONJ的病理生理学存在高度争议，最可能是由于BP的多效性作用。最近，我们已经证明，由于BP管理破骨细胞功能障碍的小鼠表现ONJ样病变约30%的时间后拔牙。虽然该领域的许多小组正在努力了解破骨细胞功能障碍如何导致BRONJ，但我们已经发现，破骨细胞功能减弱是必需的，但不足以诱导BRONJ。为了了解BRONJ发展中涉及的其他因素，我们通过对活检组织进行微阵列分析，确定了潜在的相关基因，特别是IL-36。我们已经在体外和体内验证了该测定的结果，表明诱导IL 36导致细胞外基质蛋白（即胶原前体）的抑制，其是伤口愈合期间再上皮化所需的，并且这种抑制可能是BRONJ发展的病因学因素。我们研究的长期目标是了解引起BRONJ的分子机制，并利用这种疾病模型更好地了解骨粘液瘤伤口愈合。在目前的研究中，我提出了一个假设，即IL-36是一个关键的细胞因子参与ONJ的发展和IL-36信号通路抑制骨形成和伤口愈合通过NF-κ B及其下游介质。基于我们的初步数据，我的目标是：1）确定IL-36抑制胶原表达的机制; 2）研究IL- 36信号转导在体内的直接作用; 3）研究IL-36对胶原表达的影响。 表达作为BRONJ诱导的危险因素。BRONJ的问题不能通过减少或取消治疗来解决，因为基础疾病（例如骨质疏松症、转移性癌症）更严重，必须加以解决。因此，确定BRONJ发生的原因，如何预测其发生，并建立治疗方法对于那些 会经历这种情况。成功完成目前的项目将解决所有这些问题，并作出重大贡献，了解这种痛苦的疾病的发病机制。该奖项将为学员作为伤口愈合和骨生物学独立研究人员的学术生涯做好准备。