Oral Mucosa Barrier and Bisphosphonate-related Osteonecrosis of the Jaw

描述（由申请人提供）：双膦酸盐（BP）治疗已被证明是有效的管理恶性肿瘤，居住或转移到骨，包括多发性骨髓瘤和乳腺癌或前列腺癌，分别。近年来，有许多病例报告了含氮BP治疗后颌骨骨坏死（ONJ）。本项目的长期目标是明确BP相关性onj的病理机制，寻找有效的预防和治疗手段。ONJ几乎只发生在口腔，在那里颌骨和口腔黏膜的界面很近。口腔黏膜具有独特的适应性免疫和先天免疫。虽然口腔黏膜提供了最有效的屏障功能之一，但过度激活的炎症/免疫反应与口腔中的各种组织损伤有关。因此，我们假设BP治疗可能异常激活口腔屏障组织的粘膜免疫，从而产生细胞毒性环境，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。活化的屏障组织淋巴细胞可以调节上皮的完整性和协调炎症反应。在SA1中，我们建议识别

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.