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: 8539768
• 负责人: ICHIRO NISHIMURA
• 金额: $ 36.96万
• 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/8539768
• 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; public health relevance; 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.

描述(由申请人提供)：双膦(BP)治疗已被证明在治疗驻留在骨中或转移到骨的恶性肿瘤方面有效，包括多发性骨髓瘤和乳腺癌或前列腺癌。近年来，有许多病例报道了含氮BP治疗后的颌骨骨坏死(ONJ)。本项目的长期目标是确定BP相关ONJ的发病机制，并开发有效的预防和治疗手段。ONJ几乎只发生在口腔，颌骨和口腔粘膜的交界处非常接近。口腔粘膜具有独特的获得性免疫和先天免疫。虽然口腔黏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，我们推测BP治疗可能会异常激活口腔屏障组织的粘膜免疫，从而产生导致骨坏死的细胞毒环境。屏障组织含有一组淋巴细胞，由T细胞、NK细胞、NKT细胞和/或Th17细胞组成。活化的屏障组织淋巴细胞可以调节上皮完整性，协调炎症反应。在SA1中，我们建议确定 候选免疫效应细胞参与了ONJ的病理机制。最近，Pi的团队开发了一种ONJ的小鼠模型，它表现出一致的坏死颌骨，相当于人类疾病。在本项目中，ONJ小鼠模型将与B/T细胞基因敲除(RAG1-/-)小鼠以及B/T/NK细胞基因敲除(RAG2/？(C)-/-)小鼠相结合，以表征ONJ的表型。在屏障组织淋巴细胞中，T细胞是应激诱导信号的第一反应细胞。在这个项目中，我们使用T细胞敲除(TCRD-/-)小鼠分别检测了口腔T细胞在ONJ病变发展中的作用。一个重要的问题仍然存在：BP治疗和激活口服屏障免疫之间的独特联系是什么？通过骨吸收，BP被破骨细胞(OCs)内化，并干扰甲羟戊酸途径，导致OCS过早失活。早期的啮齿动物ONJ病变显示出一群不寻常的炎性细胞并列在受BP影响的OCS上。这一观察结果使我们假设，血压受损的OCS是应激信号的细胞来源，激活口腔屏障免疫效应细胞，从而启动ONJ的发病机制。在SA2中，我们建议建立一种包含BP吸收的帽盘和人单核细胞来源的OCS的体外模型。通过共培养系统对人口腔淋巴细胞和外周血淋巴细胞的影响进行差异性评价。本项目的研究结果可能为研究口腔黏膜屏障免疫效应细胞和药物调控OCS的应激信号机制开辟新的途径，并为ONJ的治疗策略提供依据。