Oral Mucosa Barrier and Bisphosphonate-related Osteonecrosis of the Jaw

口腔粘膜屏障和双磷酸盐相关的颌骨坏死

• 批准号: 8432953
• 负责人: ICHIRO NISHIMURA
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-04 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8432953
• 关键词: Address; Affect; Area; Bacterial Infections; Bone Resorption; Bone Surface; Bone necrosis; CD8B1 gene; Case Study; Cell Culture System; Cells; Cessation of life; Chemicals; Coculture Techniques; Complication; Conditioned Culture Media; Culture Media; Dense Connective Tissue; Development; Disease; Distress; Effector Cell; Environment; Epithelial; Exhibits; Exposure to; Generations; Human; Immune; Immune system; Immunity; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Infiltrate; Injury; Investigation; Jaw; Jaw Abnormalities; Knock-out; Left; Lesion; Link; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of prostate; Mandible; Maxilla; Mediating; Modality; Modeling; Molecular Profiling; Mucosal Immunity; Multiple Myeloma; Mus; Natural Immunity; Natural Killer Cells; Necrosis; Neoplasm Metastasis; Nitrogen; Oral; Oral cavity; Oral mucous membrane structure; Osteoclasts; Osteocytes; Outcome; Outcome Study; Pain; Pathogenesis; Pathway interactions; Patients; Peripheral; Peripheral Blood Lymphocyte; Phenotype; Play; Prevalence; Prevention; Preventive; Property; Rattus; Reaction; Recovery; Respondent; Rodent; Role; Signal Transduction; Source; Stratified Epithelium; Stress; Symptoms; System; T-Lymphocyte; TRD@ gene cluster; Therapeutic; Tissues; Tooth Extraction; Zoledronate; adaptive immunity; alveolar bone; base; bisphosphonate; bone; bone cell; cytokine; cytotoxic; early onset; experience; human disease; in vitro Model; intravenous injection; keratinocyte; malignant breast neoplasm; mevalonate; monocyte; mouse model; osteoclastogenesis; premature; wound

DESCRIPTION (provided by applicant): Bisphosphonate (BP) treatment has been shown to be effective in the management of malignant neoplasms that reside in or metastasize to bone, including multiple myeloma and breast or prostate cancer, respectively. In the recent years, there have been a number of cases reporting osteonecrosis of the jaw (ONJ) subsequent to nitrogen-containing BP treatment. The long-term objective of this project is to determine the pathological mechanism of BP associated-ONJ and to develop effective means for prevention and treatment. ONJ occurs nearly exclusively in the oral cavity, where jawbone and oral mucosa interface at a close proximity. Oral mucosa is equipped with the unique subset of adaptive and innate immunity. While oral mucosa provides one of the most effective barrier functions, over-activation of inflammatory/immune reactions has been linked to various tissue damages in the oral cavity. Therefore, we postulate that BP treatment may abnormally activate the mucosal immunity of oral barrier tissue resulting in generating a cytotoxic environment leading to osteonecrosis. The barrier tissues contain a set of lymphocytes composed of ¿¿ T cells, NK cells, NKT cells and/or Th17 cells. Activated barrier tissue lymphocytes can regulate the epithelial integrity and orchestrate inflammatory reactions. In SA1, we propose to identify the candidate immune effector cells involved in the pathological mechanism of ONJ. Recently, PI's team developed a mouse model of ONJ, which exhibited consistent necrotic jawbones, equivalent to the human disease. In this project, the mouse ONJ model will be combined with B/T cell knockout (RAG1-/-) mice as well as B/T/NK cell knockout (RAG2/?(c)-/-) mice, in which the ONJ phenotype will be characterized. Among the barrier tissue lymphocytes, ?¿ T cells present the first respondent to stress-induced signals. In this project, we separately examine the role of oral ?¿ T cells in the development of ONJ lesions using ?¿ T cell-knockout (TCRD-/-) mice. An important question still remains: what is the unique link between BP treatment and the activation of oral barrier immunity? Through bone resorption, BP is internalized by osteoclasts (OCs) and interferes the mevalonate pathway leading to premature inactivation of OCs. The early onset of rodent ONJ lesions demonstrated an unusual cluster of inflammatory cells juxtaposing BP-distressed OCs. This observation has led us to hypothesize that BP-distressed OCs are the cellular source of stress signals activating oral barrier immune effector cells and thus initiating ONJ pathogenesis. In SA2, we propose to establish an in vitro model involving BP-absorbed CaP disc and human monocyte-derived OCs. The effect of BP-distressed OCs on human oral lymphocytes or peripheral blood lymphocytes will be differentially evaluated by co-culture system. The outcome of this project may open a new avenue of investigations on oral mucosa barrier immune effector cells and previously unexplored stress signaling mechanisms of the pharmacologically manipulated OCs and provide the basis for therapeutic strategy of ONJ. PUBLIC HEALTH RELEVANCE: In recent years, there are increasing numbers of patients treated with bisphosphonates, who have experienced osteonecrosis (bone death) in maxilla or mandible. This study will investigate the cause of osteonecrosis of the jaw in a mouse model and cell culture systems. The outcome of this study should provide a basis for potential treatments for those suffering from this disease.

描述（由适用提供）：双膦酸盐（BP）治疗已被证明可有效地管理驻留或转移到骨骼或转移到骨骼的恶性肿瘤，包括多个骨髓瘤，乳腺癌或前列腺癌。近年来，有许多病例报告了含氮的BP治疗后的颌骨（ONJ）的骨坏死。该项目的长期目的是确定BP相关-INJ的病理机制，并开发有效的预防和治疗方法。 ONJ几乎完全出现在口腔中，颚骨和口服粘膜界面紧密接近。口服粘膜等效于适应性和先天免疫史的独特子集。尽管口服粘膜提供了最有效的屏障功能之一，但炎症/免疫反应的过度激活与口腔中的各种组织损伤有关。因此，我们假设BP治疗可能绝对激活口腔屏障组织的粘膜免疫，从而产生细胞毒性环境，从而导致截骨性。屏障组织包含一组由``T细胞，NK细胞，NKT细胞和/或TH17细胞组成的淋巴细胞。活化的屏障组织淋巴细胞可以调节上皮完整性并编排炎症反应。在SA1中，我们建议确定 参与ONJ病理机制的候选免疫效应细胞。最近，Pi的团队开发了一个小鼠ONJ的模型，该模型暴露了一致的坏死Jawbones，相当于人类疾病。在此项目中，小鼠ONJ模型将与B/T细胞敲除（RAG1 - / - ）小鼠以及B/T/NK细胞敲除（RAG2/？（C） - / - ）小鼠结合使用，其中将表征ONJ表型。在屏障组织淋巴细胞中，t细胞提出了第一个对应激诱导的信号的反应。在这个项目中，我们分别检查了口服？T细胞在使用？t细胞敲除（TCRD - / - ）小鼠开发中的作用。仍然存在一个重要的问题：BP治疗与口腔屏障免疫的激活之间的独特联系是什么？通过骨骼分辨率，BP通过破骨细胞（OC）内在​​化，并干扰肠龙酸盐途径导致OC的过早失活。啮齿动物病变的早期发作表明，与BP插入的OC并列的炎性细胞异常簇。这一观察结果使我们假设BP分配的OC是应力信号激活口腔屏障免疫效应细胞的细胞来源，因此启动了ONJ发病机理。在SA2中，我们建议建立一个涉及BP吸收帽盘和人类单核细胞衍生的OC的体外模型。通过共培养系统，对BP的OC对人口服淋巴细胞或外周血淋巴细胞的影响将有所不同。该项目的结果可能会为口服粘膜屏障免疫效应细胞和以前意外的压力信号传导机制开辟新的投资途径，并为ONJ的治疗策略提供基础。 公共卫生相关性：近年来，接受双膦酸盐治疗的患者数量越来越多，这些患者在上颌骨或下颌骨中经历了骨坏死（骨死亡）。这项研究将研究小鼠模型和细胞培养系统中下颌骨坏死的原因。这项研究的结果应为患有这种疾病的人提供潜在治疗的基础。