Osteocyte Death in Osteonecrosis of the Jaw in Rice Rats: Role of Necroptosis and Temporal Relationship with Radiographic, Molecular and Histopathologic Findings

水稻大鼠下颌骨坏死中的骨细胞死亡：坏死性凋亡的作用以及与放射学、分子和组织病理学结果的时间关系

• 批准号: 10532069
• 负责人: Jose Ignacio Aguirre
• 金额: $ 23.56万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532069
• 关键词: Affect; Angiogenesis Inhibitors; Animal Model; Apoptosis; Apoptotic; Applications Grants; Attention; Bone necrosis; Cancer Patient; Cell Death; Cessation of life; Clinical; Clinical Research; Clinical Trials; Control Groups; Data; Development; Diagnostic; Disease; Disease Outcome; Disseminated Malignant Neoplasm; Fostering; Foundations; Functional disorder; Health; High Prevalence; Histology; Histopathology; Human; Immune response; Immunohistochemistry; Incidence; Infection; Inflammation; Inflammatory; Intervention; Investigation; Jaw; Knowledge; Life; Link; Malignant Neoplasms; Maxilla; Mission; Modality; Modeling; Molecular; Molecular Genetics; Monitor; Mucous Membrane; Necrosis; Oral; Oral cavity; Oral health; Oral mucous membrane structure; Osteocytes; Osteoporosis; Outcome Study; Pain; Pathogenesis; Pathologic; Patients; Pattern; Pattern recognition receptor; Periodontitis; Pharmaceutical Preparations; Pharmacology; Play; Prevalence; Process; Public Health; Radiation therapy; Radiology Specialty; Rattus; Recording of previous events; Research; Rice Rats; Risk Factors; Role; Saline; Scanning; Shapes; Signal Pathway; Site; Subgroup; Testing; Therapeutic; Therapeutic Intervention; Time; TimeLine; Tissues; Tooth Extraction; United States National Institutes of Health; Zoledronic Acid; base; bone; burden of illness; cell type; clinical development; clinical predictors; defined contribution; disability; genetic approach; genetic testing; health related quality of life; improved; in vivo; inflammatory marker; inhibitor; innovation; microCT; molecular marker; novel; novel therapeutics; oral infection; periapical; pre-clinical research; preclinical study; prevent; primary outcome; radiological imaging; skeletal; targeted treatment

PROJECT SUMMARY/ABSTRACT Osteonecrosis of the jaw (ONJ) is a potentially severe, debilitating condition affecting the mouth of patients with cancer or osteoporosis who have taken antiresorptive drugs, like zoledronic acid (ZOL) or denosumab, and concurrently have an oral risk factor such as tooth extraction, periodontitis, or periapical infection. Clinical ONJ (stages 1-3) is defined by the presence of exposed dead bone in the jaw for longer than 8wks in patients with no history of radiation therapy or metastatic cancer to the jaws. In contrast, early-stage ONJ (stage 0) lacks exposed bone, demonstrating intermittent pain and nonspecific radiographic findings. Whether the necrotic jaw bone with its dead osteocytes is present in the early stages, while the oral mucosa still covers the underlying tissues, or occurs only after it becomes exposed, remains to be determined. Further, the type(s) of cell death affecting osteocytes in ONJ is not completely elucidated. Understanding whether osteocyte death is a feature already present in stage 0 may represent a key first step to finding new therapies for ONJ. Indeed, early pharmacologic interventions that avert osteocyte death while oral risk factors are being removed could prevent ONJ. Gaps in knowledge limit the ability to identify ONJ in its earliest stages and intervene to stop its progression. The critical role of osteocyte apoptosis in the pathophysiology of various skeletal conditions has been substantiated. However, little attention has been paid to necroptosis, a specific “regulated” form of cell death triggered by inflammation, such as that associated with periodontitis and periapical infection. Unlike apoptosis, necroptosis enhances immune responses and inflammation. Notably, ZOL treated rats developing ONJ showed increased necroptosis, but not apoptosis, in osteocytes. Pharmacologic inhibitors targeting specific regulatory components of necroptosis have been developed. Some are now in clinical trials to treat inflammatory diseases. Thus, we hypothesize that: 1) osteocyte death occurs before bone exposure in ONJ; 2) osteocyte death occurs in temporal association with specific radiologic, cellular, and molecular features; and 3) necroptosis is the dominant type of cell death involved in ONJ. Our approach is to use rice rats with localized periodontitis that can be easily monitored by oral exams and start treating them with ZOL to determine: Aim 1: the timing and type(s) of cell death affecting osteocytes in the early stages of ONJ and the temporal relationship of osteocyte death to radiographic, cellular, and molecular findings; and Aim2: the contribution of necroptosis and apoptosis in the development of clinical ONJ in rice rats using pharmacologic inhibitors. The study outcomes will define temporally and mechanistically the prodrome of ONJ, potentially stage 0 in humans, supporting the development of targeted therapies to halt osteocyte death, and establish direct evidence for the role of necroptosis to ONJ and in vivo proof of concept for the therapeutic potential of inhibiting components of its signaling pathway from halting ONJ progression.

项目摘要/摘要 颌骨（ONJ）的骨坏死是一种潜在的严重，令人衰弱的状况，影响了患者的口腔 服用抗吸毒药物的癌症或骨质疏松症，例如唑来膦酸（ZOL）或denosumab， 并同时具有口服危险因素，例如拔牙，牙周炎或周围感染。临床 ONJ（第1-3阶段）是通过在患者中存在超过8周的下颌中存在暴露的死骨来定义的。 没有放射治疗或下颌转移性癌的史。相比之下，早期ONJ（阶段0） 缺乏裸露的骨头，表现出间歇性疼痛和非特异性射线照相发现。是否 坏死的颌骨及其死骨细胞在早期存在，而口服粘膜仍然覆盖 潜在的组织，或仅在暴露后才发生，仍有待确定。此外，类型 影响ONJ中骨细胞的细胞死亡并未完全阐明。了解骨细胞死亡是否是 第0阶段中已经存在的功能可能代表寻找ONJ的新疗法的关键第一步。的确， 消除口服危险因素时避免骨细胞死亡的早期药理干预措施可能 防止ONJ。知识的差距限制了在其最早阶段识别ONJ的能力，并干预以停止其 进展。骨细胞凋亡在各种骨骼状况的病理生理学中的关键作用 得到了证实。但是，很少关注坏死性，这是一种特定的“调节”细胞形式 由炎症引起的死亡，例如与牙周炎和周围感染有关的死亡。与众不同 凋亡，坏死性增强了免疫反应和炎症。值得注意的是，佐尔治疗的老鼠发育 ONJ在骨细胞中显示出坏死的增加，但没有凋亡。药理抑制剂靶向 已经开发了坏死性的特定调节成分。现在有些正在接受临床试验以治疗 炎症性疾病。那就是我们假设的：1）骨细胞死亡发生在骨头暴露之前 onj; 2）骨细胞死亡发生在临时关联与特定的放射学，细胞和 分子特征； 3）坏死性是ONJ涉及的细胞死亡的主要类型。我们的方法 是使用含有局部牙周炎的米大鼠，可以通过口腔检查轻松监测并开始治疗 用ZOL确定： 目标1： 细胞死亡的时间和类型影响骨细胞的早期阶段 ONJ和骨细胞死亡与放射线，细胞和分子发现的临时关系；和 AIM2： 坏死性和凋亡在使用水稻大鼠临床开发中的贡献 药理抑制剂。研究结果将暂时和机械地定义ONJ的前代， 潜在的人类中的第0阶段，支持靶向疗法的发展，以阻止骨细胞死亡和 建立直接证据证明坏死性对ONJ和体内概念验证的作用 抑制其信号传导途径的组件阻止ONJ进展的潜力。