Role of Periodontitis in Osteonecrosis of the Jaw Pathophysiology in Rice Rats

牙周炎在水稻大鼠下颌骨坏死病理生理学中的作用

• 批准号: 9321219
• 负责人: Jose Ignacio Aguirre
• 金额: $ 33.62万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321219
• 关键词: Affect; Animal Model; Antibodies; Appearance; Autopsy; Bone necrosis; Cancer Patient; Case Series; Categories; Clinical; Clinical Research; Clinical Trials; Comorbidity; Data; Dental; Detection; Development; Dose; Edentulous Mouth; Enabling Factors; Epithelial; Epithelial Cell Proliferation; Epithelium; Event; Excision; Fostering; Functional disorder; Future; Gingiva; Goals; Health; Histologic; Histology; Human; Impaired wound healing; Incidence; Incidental Findings; Infection; Inflammation; Jaw; Knowledge; Lesion; Life; Link; Mandible; Maxilla; Mission; Mucous Membrane; Nature; Necrosis; Nitrogen; Oral; Oral cavity; Oryzomys; Outcome; Pathogenesis; Pathologic; Patients; Periodontitis; Persons; Population; Prevention; Process; Proliferation Marker; Public Health; Rattus; Reporting; Research; Rice Rats; Risk; Risk Factors; Role; Sampling; Site; TNFSF11 gene; Testing; Thick; Thinness; Time; Tissues; Tooth Extraction; Tooth structure; United States National Institutes of Health; Zoledronic Acid; alveolar bone; base; bisphosphonate; bone; burden of illness; cofactor; design; disability; experimental study; healing; improved; innovation; killings; older patient; oncology; pre-clinical; prospective; public health relevance

DESCRIPTION (provided by applicant): Anti-resorptive-related osteonecrosis of the jaw (ARONJ) occurs in human cancer patients treated with powerful anti-resorptives (pAR) including zoledronic acid (ZOL) and denosumab. The low incidence of ARONJ (~2%) suggests that pARs are necessary, but not by themselves sufficient to cause ARONJ. ~75% of ARONJ patients report a recent discrete oral event, most often tooth extraction ("event-related"), leaving ~25% of ARONJ patients in the "spontaneous" category. In fifth decade and older humans, ~1/3 of tooth extractions involve periodontally-involved teeth. Periodontitis (PD) is an incidental finding in many ARONJ case series. These two facts suggest that instead of being just a random finding, PD is an intervening factor that promotes "spontaneous" and "event-related" ARONJ in persons taking pARs. Though clinical studies suggest that ARONJ risk increases with dose and duration of pAR treatment, no confirmatory preclinical experiments have been conducted. We refined the rice rat, an animal model of naturally developing moderate-severe PD (R03), in which oncology doses of ZOL (HD-ZOL) induce ARONJ-like lesions. We also showed reduced gingival epithelial proliferation and gingival thinning in HD-ZOL treated rats. Our central hypothesis is that ARONJ is a three-step process: a) dental factors (e.g., PD, extraction of periodontally-infected teeth) induce inflammation/infection and accelerated oral hard tissue necrosis, b) pARs slow the removal of the necrotic bone, and reduce gingival epithelial proliferation and cause gingival thinning, resulting in c) necrotic alveolar bone accumulation that leads to a loss of gingival mucosa overlying bone, exposure of dead bone to the oral cavity, and the appearance of an ARONJ lesion. Guided by strong preliminary data, this hypothesis will be tested by two specific aims: Aim #1: determine the roles of periodontitis and pARs in the development of ARONJ-like lesions in rice rats by conducting three experiments to assess the incidence rate of ARONJ-like lesions in relation to: a) dose and exposure time to ZOL (Exp 1), b) degree of PD (Exp 1&2), and c) influence of preexisting PD on post-extraction healing, including development of ARONJ (Exp 3). We will determine PD degree and identify ARONJ-like lesions grossly, by histology and �CT to establish these associations and incidence rates. Aim #2: Determine the effects of ZOL on the gingival epithelium of rice rats by assessing gingival epithelial proliferation and thicknes in rats after different ZOL doses for different durations. The proposed research is expected to demonstrate that: a) moderate/severe PD is an enabling factor for ARONJ; b) dose and exposure time to pARs affect the incidence of ARONJ-like lesions, and c) ZOL decreases gingival thickness and proliferation. These outcomes will have a positive impact because they will: a) disclose key avenues for prevention/treatment of ARONJ; b) more firmly disclose/establish the nature of the causal relationship of pARs and PD to ARONJ to build a rationale for future clinical trials that explore dosing and treatment intervals of pARs in patient with varying levels of PD, and c) disclose an alternative tissue action site for ZOL that may explain another type of spontaneous ARONJ.

描述（由申请人提供）：抗吸收相关性颌骨坏死（ARONJ）发生在接受强效抗吸收药物（pAR）（包括唑来膦酸（ZOL）和狄诺塞麦）治疗的人类癌症患者中。 ARONJ 的低发生率 (~2%) 表明 pAR 是必要的，但其本身不足以引起 ARONJ。约 75% 的 ARONJ 患者报告近期发生过离散口腔事件，最常见的是拔牙（“事件相关”），约 25% ARONJ 患者属于“自发性”类别。在 50 岁及以上的人类中，约 1/3 的拔牙涉及牙周病牙齿。牙周炎 (PD) 是许多 ARONJ 病例系列中的偶然发现。这两个事实表明，PD 不仅仅是一个随机发现，而是一个促进服用 pAR 的人“自发”和“事件相关”ARONJ 的干预因素。尽管临床研究表明 ARONJ 风险随着 pAR 治疗剂量和持续时间的增加而增加，但尚未进行验证性临床前实验。我们改进了水稻大鼠，这是一种自然发展的中重度 PD (R03) 动物模型，其中肿瘤剂量的 ZOL (HD-ZOL) 诱导 ARONJ 样病变。我们还发现，HD-ZOL 治疗的大鼠牙龈上皮增殖减少，牙龈变薄。我们的中心假设是ARONJ是一个三步过程：a）牙科因素（例如PD、拔除牙周感染的牙齿）诱发炎症/感染并加速口腔硬组织坏死，b）pARs减缓坏死骨的去除，并减少牙龈上皮增殖并导致牙龈变薄，导致c）坏死的牙槽骨堆积，导致 覆盖骨的牙龈粘膜缺失、死骨暴露于口腔以及出现 ARONJ 病变。在强有力的初步数据指导下，这一假设将通过两个具体目标进行检验： 目标#1：通过进行三项实验来评估 ARONJ 样病变的发生率，确定牙周炎和 pAR 在水稻大鼠 ARONJ 样病变发展中的作用：a) ZOL 的剂量和暴露时间（实验 1），b）PD 程度（实验 1 和 2），c）PD 的影响 拔牙后愈合中先前存在的 PD，包括 ARONJ 的发展（实验 3）。我们将通过组织学和 CT 确定 PD 程度并粗略识别 ARONJ 样病变，以确定这些关联和发生率。目标#2：通过评估不同 ZOL 剂量不同持续时间后大鼠的牙龈上皮增殖和厚度，确定 ZOL 对水稻大鼠牙龈上皮的影响。拟议的研究预计将证明： a) 中度/重度 PD 是 ARONJ 的促成因素； b) pAR 的剂量和暴露时间影响 ARONJ 样病变的发生率，c) ZOL 降低牙龈厚度和增殖。这些结果将产生积极影响，因为它们将： a) 披露预防/治疗 ARONJ 的关键途径； b) 更坚定地披露/建立 pAR 和 PD 与 ARONJ 因果关系的性质，为未来的临床试验奠定基础，探索 pAR 在不同 PD 水平患者中的给药和治疗间隔，以及 c) 披露 ZOL 的替代组织作用位点，这可能解释另一种类型的自发性 ARONJ。