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: 8705268
• 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/8705268
• 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）：双膦酸盐（BP）治疗已被证明可有效治疗骨内或转移至骨的恶性肿瘤，分别包括多发性骨髓瘤和乳腺癌或前列腺癌。近年来，已有多起接受含氮BP治疗后发生颌骨坏死（ONJ）的病例。该项目的长期目标是确定BP相关ONJ的病理机制并开发有效的预防和治疗手段。 ONJ 几乎只发生在口腔，颌骨和口腔粘膜在此交界处非常接近。口腔粘膜具有独特的适应性和先天免疫子集。虽然口腔粘膜提供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治疗可能异常激活口腔屏障组织的粘膜免疫，导致产生细胞毒性环境，导致骨坏死。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。激活的屏障组织淋巴细胞可以调节上皮完整性并协调炎症反应。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的团队开发了一种ONJ小鼠模型，该模型表现出一致的颌骨坏死，与人类疾病相当。在该项目中，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)-/-）小鼠相结合，其中ONJ表型将被表征。在屏障组织淋巴细胞中，T 细胞是对应激诱导信号的第一个反应者。在这个项目中，我们使用 TCRD-/- 小鼠分别研究了口腔 T 细胞在 ONJ 病变发展中的作用。 仍然存在一个重要的问题：血压治疗与口腔屏障免疫激活之间的独特联系是什么？通过骨吸收，BP 被破骨细胞 (OC) 内化并干扰甲羟戊酸途径，导致 OC 过早失活。啮齿类动物 ONJ 病变的早期发作表明，有一组不寻常的炎症细胞与 BP 应激的 OC 并列。这一观察结果使我们推测，BP 应激的 OC 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 发病机制。在SA2中，我们建议建立一个涉及BP吸收的CaP盘和人单核细胞衍生的OC的体外模型。 BP应激OCs对人口腔淋巴细胞或外周血淋巴细胞的影响将通过共培养系统进行差异评估。 该项目的成果可能为口腔粘膜屏障免疫效应细胞和以前未探索的药理操纵OC的应激信号传导机制开辟一条新的研究途径，并为ONJ的治疗策略提供基础。