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: 10689159
• 负责人: Jose Ignacio Aguirre
• 金额: $ 18.43万
• 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/10689159
• 关键词: Accidents; Affect; Angiogenesis Inhibitors; Animal Model; Apoptosis; Apoptotic; Applications Grants; Attention; Bone necrosis; Cancer Patient; Cell Death; Cessation of life; Classification; Clinical; Clinical Research; Clinical Trials; Control Groups; Creativeness; Data; Development; Diagnostic; Disease; Disease Outcome; Disseminated Malignant Neoplasm; Early identification; Euthanasia; 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; 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; 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; Tissues; Tooth Extraction; United States National Institutes of Health; X-Ray Computed Tomography; Zoledronic Acid; bone; burden of illness; cell type; clinical development; clinical predictors; defined contribution; disability; feature detection; 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; pharmacologic; pre-clinical research; preclinical study; prevent; primary outcome; radiological imaging; skeletal; targeted treatment; timeline

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.

项目概要/摘要 颌骨坏死 (ONJ) 是一种影响患者口腔的潜在严重、衰弱性疾病 患有癌症或骨质疏松症，服用抗骨吸收药物，如唑来膦酸 (ZOL) 或狄诺塞麦， 同时存在口腔危险因素，如拔牙、牙周炎或根尖周感染。 ONJ（1-3 期）是指患者下颌存在暴露的死骨超过 8 周 没有放射治疗史或颌骨转移性癌症相反，早期ONJ（0期）。 缺乏暴露的骨骼，表现出间歇性疼痛和非特异性放射学检查结果。 早期即出现颌骨坏死及其死骨细胞，而口腔粘膜仍覆盖颌骨。 底层组织，或仅在暴露后发生，还有待确定。 细胞死亡对 ONJ 中骨细胞的影响尚未完全阐明。 0 阶段已经存在的功能可能代表寻找 ONJ 新疗法的关键第一步。 早期药物干预可避免骨细胞死亡，同时消除口腔危险因素 预防 ONJ 知识差距限制了在早期阶段识别 ONJ 并进行干预以阻止其发生的能力。 骨细胞凋亡进展在各种骨骼疾病的病理生理学中发挥着关键作用 然而，人们很少关注坏死性凋亡（一种特殊的“调节”细胞形式）。 由炎症引发的死亡，例如与牙周炎和根尖周感染相关的炎症。 细胞凋亡、坏死性凋亡增强了免疫反应和炎症。值得注意的是，ZOL 治疗的大鼠正在发育。 ONJ 在骨细胞中显示出坏死性凋亡增加，但不增加细胞凋亡。 坏死性凋亡的特定调节成分已经开发出来，其中一些目前正在临床试验中进行治疗。 因此，我们认为：1）骨细胞死亡发生在骨暴露之前。 ONJ；2) 骨细胞死亡与特定的放射学、细胞学和 分子特征；3) 坏死性凋亡是 ONJ 中涉及的主要细胞死亡类型。 是使用患有局部牙周炎的稻鼠，通过口腔检查很容易监测到并开始治疗它们 用 ZOL 确定： 目标 1： 早期阶段影响骨细胞的细胞死亡的时间和类型 ONJ 以及骨细胞死亡与放射学、细胞和分子结果的时间关系； 目标2： 稻鼠坏死性凋亡和细胞凋亡在临床ONJ发展中的作用 研究结果将在时间上和机械上定义 ONJ 的前驱症状， 人类可能处于 0 阶段，支持开发阻止骨细胞死亡的靶向疗法，以及 建立坏死性凋亡对 ONJ 作用的直接证据以及治疗概念的体内证明 抑制其信号通路成分以阻止 ONJ 进展的潜力。