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

基本信息

批准号：
10119690
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
项目类别：
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/10119690
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 Epithelium 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 Treatment Efficacy 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 translational study

项目摘要

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.

抗吸收性药物，尤其是双膦酸盐（BP）和denosumab是有效的抑制剂破骨细胞功能，用于管理骨骼疾病，例如骨恶性肿瘤或骨质疏松症。尽管在临床上很重要，但这些药物与药物相关的截至下巴（mronj）是一种罕见但严重的副作用，可能会导致衰弱的疼痛和发病率。而且，恐惧开发MRONJ已导致患者遵守抗吸收性使用的逐步下降，以及骨质疏松症的危机危机。改善MRONJ预防，诊断和治疗将具有对骨骼疾病患者的医疗保健的巨大影响。根据父母赠款支持的研究建立了良好的临床医生跨学科团队为 MRONJ的病理生理，诊断和管理。总体而言，我们的研究提供了重要的洞悉MRONJ发病机理。在患有牙齿疾病的对照动物中，骨骼有远离炎症性nidus。相反，破骨细胞抑制会导致骨骼暴露于炎症，并导致与炎症灶相邻的骨坏死。上皮迁移发生在对照和抗吸收性中治疗的动物。然而，随着骨吸收的抑制，上皮朝向肺泡波峰，最终使坏死骨束，导致骨骼暴露。用牙齿提取牙齿疾病，导致明显的mronj。相比之下，在动物中提取健康牙齿后可以实现抗吸收粘膜和插座愈合。通过我们的研究，我们发展了通过诱导实验性牙周或根尖性疾病和在没有牙齿的情况下，用高剂量抗吸收剂治疗。这些模型捕获早期组织 MRONJ启动期间的变化。根据我们发表的初步发现，我们假设最终导致临床暴露骨的病理生理框架的启动涉及垂死的骨细胞，挑战软组织稳态和免疫反应扭曲的相互作用。我们的目的是确定MRONJ启动和进展的早期病理生理机制以及采取有效的治疗干预措施。为了满足我们的目标并检验我们的假设，我们提出了三个具体目标。 AIM 1：确定HMGB1从坏死骨细胞释放的程度有助于 MRONJ启动和进展目标2：描述巨噬细胞参与MRONJ启动和进展。 AIM 3：定义巨噬细胞和骨细胞血红素 - 氧合酶-1（HO-1）在MRONJ中的作用启动和进展。