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

描述(申请人提供)：抗吸收相关颌骨坏死(ARONJ)发生在接受包括唑来膦酸(ZOL)和地诺单抗(Denosumab)在内的强大抗吸收药物(PAR)治疗的人类癌症患者中。ARONJ的发生率很低(~2%)，提示PARs是必要的，但本身并不足以导致ARONJ。约75%的ARONJ患者报告了最近发生的离散口腔事件，最常见的是拔牙(与事件相关)，留下约25%的 ARONJ患者属于“自发”类别。在50岁及以上的人类中，约1/3的拔牙涉及牙周病变。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，帕金森病不只是一个随机的发现，而是一个介入性因素，它促进了参与PARS的人的“自发”和“事件相关”ARONJ。尽管临床研究表明ARONJ的风险随着PAR治疗的剂量和持续时间的增加而增加，但还没有进行验证性的临床前实验。我们提炼了大米大鼠，这是一种自然发展为中重度帕金森病(R03)的动物模型，在该模型中，肿瘤剂量的ZOL(HD-ZOL)诱导了ARONJ样病变。我们还发现HD-ZOL治疗的大鼠牙龈上皮细胞增殖减少，牙龈变薄。我们的中心假设是，ARONJ是一个由三个步骤组成的过程：a)牙科因素(如牙周感染牙齿的拔除)引起炎症/感染和加速口腔硬组织坏死，b)PARS减慢坏死骨的移除，减少牙龈上皮细胞的增殖和引起牙龈变薄，导致c)坏死性牙槽骨积聚，导致覆盖在骨上的牙龈粘膜丧失，死骨暴露在口腔内，以及ARONJ病变的出现。在强大的初步数据指导下，这一假说将被两个特定的目标验证：目的1：通过开展三个实验来评估ARONJ样病变的发生率，以确定牙周炎和PARS在水稻大鼠ARONJ样病变发生中的作用：a)ZOL的剂量和暴露时间(实验1)，b)PD的程度(实验1和2)，以及c)预先存在的PD对拔牙后愈合的影响，包括ARONJ的发展(实验3)。我们将通过组织学和�CT确定帕金森病的程度，并大体识别ARONJ样病变，以建立这些相关性和发病率。目的#2：观察不同剂量ZOL作用不同时间对大鼠牙龈上皮细胞增殖和增厚的影响，探讨ZOL对大鼠牙龈上皮细胞的影响。这项拟议的研究有望证明：a)中/重度PD是ARONJ的一个促成因素；b)暴露于PARS的剂量和时间影响ARONJ样病变的发生率，以及c)ZOL减少牙龈厚度和增殖。这些结果将产生积极的影响，因为它们将：a)揭示预防/治疗ARONJ的关键途径；b)更确切地披露/确立PARS和PD与ARONJ之间因果关系的性质，从而为未来的临床试验探索PARS的剂量和治疗间隔奠定基础；以及c)揭示ZOL的替代组织作用部位，可能解释另一种类型的自发性ARONJ。

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.