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: 9114089
• 负责人: Jose Ignacio Aguirre
• 金额: $ 37.74万
• 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/9114089
• 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; Healed; Health; Histologic; Histology; Human; Impaired wound healing; Incidence; Incidental Findings; Infection; Inflammation; Jaw; Knowledge; Left; 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; Staging; TNFSF11 gene; TRANCE protein; Testing; Thick; Time; Tissues; Tooth Extraction; Tooth structure; Work; Zoledronic Acid; alveolar bone; base; bisphosphonate; bone; burden of illness; cofactor; design; disability; healing; improved; innovation; killings; older patient; oncology; oral infection; pre-clinical; prospective; public health relevance; research study

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）：抗吸收相关性颌骨骨坏死（ARONJ）发生在人类癌症患者中，使用强效抗吸收药物（pAR）包括唑来膦酸（ZOL）和地诺单抗。ARONJ的低发生率（约2%）表明pARs是必要的，但本身不足以引起ARONJ。约75%的ARONJ患者报告最近发生过离散的口腔事件，最常见的是拔牙（“事件相关”），剩下约25%的ARONJ患者报告最近发生过口腔事件