Pathophysiologic mechanisms during initiation of medication related osteonecrosis of the jaws

药物相关颌骨骨坏死起始过程中的病理生理机制

• 批准号: 10264918
• 负责人: SOTIRIOS TETRADIS
• 金额: $ 36.13万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10264918
• 关键词: Address; Alveolar; Animal Model; Animals; Area; Blood Vessels; Bone Resorption; Bone Resorption Inhibition; Bone necrosis; Cells; Cessation of life; Clinical; Control Animal; Data; Development; Diagnosis; Disease; Disease Progression; Dose; Early Diagnosis; Early Intervention; Epithelial; Exposure to; Fright; Functional disorder; Genes; Goals; HMGB Proteins; HMGB1 gene; Healthcare; Homeostasis; Hypoxia; Immune response; Impairment; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Ischemia; Jaw; Lead; Lesion; Malignant Neoplasms; Medication Management; Modeling; Morbidity - disease rate; Mucous Membrane; Necrosis; Operative Surgical Procedures; Oral cavity; Osteoclasts; Osteocytes; Osteoporosis; Outcome; Oxidative Stress; Pain; Pathogenesis; Pathway interactions; Patient Care; Patients; Periapical Diseases; Periodontal Diseases; Pharmaceutical Preparations; Pharmacology; Phenotype; Prevention; Publishing; Reporting; Research; Role; Scientist; Severities; Signal Transduction; Site; Surface; Testing; Therapeutic Intervention; Tissues; Tooth Diseases; Tooth Extraction; Tooth structure; Transforming Growth Factor beta; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factors; Zoledronic Acid; base; bisphosphonate; bone; collagenase 3; compliance behavior; healing; heme oxygenase-1; improved; inflammatory milieu; inhibitor/antagonist; insight; macrophage; migration; novel; novel diagnostics; novel therapeutic intervention; parent grant; prevent; side effect; skeletal disorder; soft tissue; therapeutically effective; translational study

Antiresorptive medications, particularly bisphosphonates (BPs) and denosumab are potent inhibitors of osteoclast function and are used to manage skeletal diseases such as bone malignancy or osteoporosis. Although clinically important, these medications are associated with medication related osteonecrosis of the jaw (MRONJ), a rare but serious side effect, that can cause debilitating pain and morbidity. Moreover, the fear of developing MRONJ has contributed to a progressive decline in patient compliance with antiresorptive use, and a looming crisis in osteoporosis. Improving MRONJ prevention, diagnosis and treatment would have a great impact in health care of patients with skeletal diseases. From studies supported by the parent grant, our well-established, interdisciplinary team of clinician-scientists has made important contributions to the pathophysiology, diagnosis and management of MRONJ. Collectively, our studies have provided significant insight into MRONJ pathogenesis. In control animals with dental disease, bone resorbs away from the inflammatory nidus. In contrast, osteoclast inhibition leads to bone being exposed to inflammation, and to osteonecrosis adjacent to inflammatory foci. Epithelial migration occurs in both control and antiresorptive treated animals. However, with inhibition of bone resorption, the epithelium descends towards the alveolar crest, and eventually rims the necrotic bone, resulting in bone exposure. Extraction of teeth with dental disease, results in conspicuous MRONJ. In contrast, after extraction of healthy teeth in animals on antiresorptives mucosal and socket healing is achieved. Through our studies, we have developed and characterized animal models of MRONJ by inducing experimental periodontal or periapical disease and treating with high-dose antiresorptives, in the absence of tooth extraction. These models capture early tissue changes during MRONJ initiation. Based on our published and preliminary findings, we hypothesize that initiation of the pathophysiologic framework that eventually leads to clinically exposed bone involves an interplay among dying osteocytes, challenged soft tissue homeostasis, and a distorted immune response. Our objective is to determine the early pathophysiologic mechanisms of MRONJ initiation and progression and to pursue effective therapeutic interventions. To meet our objective and test our hypothesis, we propose three Specific Aims. Aim 1: Determine the extent to which HMGB1 released from necrosing osteocytes contributes to MRONJ initiation and progression Aim 2: Delineate macrophage involvement in MRONJ initiation and progression. Aim 3: Define the role of macrophage and osteocyte heme-oxygenase-1 (HO-1) in MRONJ initiation and progression.

抗再吸收药物，特别是双磷酸盐 (BP) 和狄诺塞麦是有效的抑制剂 破骨细胞功能并用于治疗骨骼疾病，例如骨恶性肿瘤或骨质疏松症。 尽管临床上很重要，但这些药物与药物相关的股骨头坏死有关。 下颌（MRONJ），一种罕见但严重的副作用，可能导致衰弱性疼痛和发病。此外，恐惧 发展 MRONJ 导致患者对抗骨吸收药物使用的依从性逐渐下降， 以及迫在眉睫的骨质疏松症危机。改善 MRONJ 的预防、诊断和治疗将有利于 对骨骼疾病患者的保健有很大影响。根据家长补助金支持的研究，我们 完善的跨学科临床医生科学家团队为该领域做出了重要贡献 MRONJ 的病理生理学、诊断和治疗。总的来说，我们的研究提供了重要的 深入了解 MRONJ 发病机制。在患有牙科疾病的对照动物中，骨吸收远离牙齿 炎性病灶。相反，破骨细胞抑制会导致骨骼暴露于炎症，并导致 邻近炎症灶的骨坏死。上皮迁移发生在对照和抗再吸收中 治疗的动物。然而，随着骨吸收的抑制，上皮细胞下降到牙槽骨 骨嵴，并最终覆盖坏死骨的边缘，导致骨暴露。用牙科拔牙 疾病，导致明显的 MRONJ。相比之下，在拔除动物健康牙齿后 抗再吸收剂使粘膜和牙槽愈合。通过我们的研究，我们已经发展并 通过诱导实验性牙周或根尖周疾病来表征 MRONJ 动物模型， 在不拔牙的情况下使用高剂量抗吸收剂进行治疗。这些模型捕获早期组织 MRONJ 启动期间发生变化。根据我们已发表的初步研究结果，我们假设 最终导致临床暴露骨的病理生理学框架的启动涉及 垂死的骨细胞、受到挑战的软组织稳态和扭曲的免疫反应之间的相互作用。我们的 目的是确定 MRONJ 发生和进展的早期病理生理机制，并 寻求有效的治疗干预措施。为了实现我们的目标并检验我们的假设，我们提出了三个 具体目标。目标 1：确定坏死骨细胞释放的 HMGB1 在多大程度上有助于 MRONJ 启动和进展目标 2：描绘巨噬细胞参与 MRONJ 启动和进展 进展。目标 3：明确巨噬细胞和骨细胞血红素加氧酶-1 (HO-1) 在 MRONJ 中的作用 启动和进展。