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

摘要

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 Guided by our previously published studies as well as unpublished preliminary data, we hypothesize that MRONJ pathogenesis is associated with altered osteomucosal immunity and immune cell plasticity via pathologic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.