Osteomucosal healing and immunity in medication-related osteonecrosis of the jaw

摘要 药物相关性颌骨坏死(MRONJ)是一种破坏性的、不可愈合的口腔内病变， 优先发生在长期使用抗吸收药物(ARM)后，如双磷酸盐(BPS) 或用于治疗骨质疏松症或骨恶性肿瘤的地诺舒单抗(DMAb)。MRONJ严重降低质量 对生命的危害，往往会造成衰弱的疼痛，并造成其他重大的健康问题。因为我们知道的太少了 关于MRONJ的病理生理学和目前的治疗在很大程度上是姑息的，迫切需要更好地 了解潜在的致病机制并开发有效的治疗方法。在.期间 在过去的十年里，我们的跨学科团队开发了各种MRONJ小鼠模型，结果表明 骨粘膜免疫失调是MRONJ病理生理学的主要来源。我们的长期合作 目的是了解骨粘膜免疫在MRONJ病理生理学中的基础，并评价其应用 在MRONJ临床表现之前进行靶向免疫治疗以缓解其症状。在我们之前的指导下 已发表的研究以及未发表的初步数据，我们假设MRONJ的发病机制是 与骨粘膜免疫和免疫细胞可塑性改变相关的病理放大的IL- 36/IL-23/Th17轴在炎症性口腔疾病和手臂的存在。这项提案的目标是 1)确定IL-36如何作为MRONJ发病机制的启动者；2)描述IL-36的桥梁作用 IL-23从IL-36增强MRONJ对Th17的致病性；3)确定Th17的病理作用 MRONJ进展过程中的细胞。我们建议的研究完成后，将提供基本的框架 通过免疫治疗和干预措施利用MRONJ，以供未来临床使用。

ABSTRACT Medication-related osteonecrosis of the jaw (MRONJ) is a destructive, non-healing intraoral lesion that preferentially occurs after long-term use of anti-resorptive medications (ARMs) such as bisphosphonates (BPs) or denosumab (Dmab) used for treating osteoporosis or bone malignancy. MRONJ severely diminishes quality of life, often causes debilitating pain, and imposes other significant health issues. Because so little is known about MRONJ pathophysiology and current treatments are largely palliative, there is an urgent need to better understand the underlying pathogenetic mechanisms and develop effective therapeutic modalities. During the past decade, our interdisciplinary team has developed various MRONJ mouse models, results of which point to dysregulation of osteomucosal immunity as the leading source of MRONJ pathophysiology. Our long-term goal is to understand the basis of osteomucosal immunity in MRONJ pathophysiology and evaluate the use of targeted immunotherapies to mitigate MRONJ prior to its clinical presentation. Guided by our previously published studies as well as unpublished preliminary data, we hypothesize that MRONJ pathogenesis is associated with altered osteomucosal immunity and immune cell plasticity via pathologic amplification of the IL- 36/IL-23/Th17 axis in the presence of inflammatory oral diseases and ARMs. The objectives of this proposal are: 1) to define how IL-36 functions as an initiator MRONJ pathogenesis; 2) to delineate the bridging role of IL-23 from IL-36 to augmenting Th17 pathogenicity in MRONJ; and 3) to determine the pathologic role of Th17 cells during MRONJ progression. Completion of our proposed studies will provide the foundational framework to harness MRONJ via immunotherapy and interventions for future clinical uses.