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: 10466925
• 负责人: SOTIRIOS TETRADIS
• 金额: $ 35.76万
• 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/10466925
• 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; debilitating pain; healing; heme oxygenase-1; improved; inflammatory milieu; inhibitor; 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，特别是双膦酸盐（BP）和狄诺塞单抗是有效的抑制剂， 破骨细胞功能，并用于治疗骨骼疾病，如骨恶性肿瘤或骨质疏松症。 虽然临床上很重要，但这些药物与药物相关的骨坏死有关， 颌（MRONJ），一种罕见但严重的副作用，可导致衰弱性疼痛和发病率。此外，恐惧 MRONJ的发展导致患者对抗吸收药物使用的依从性逐渐下降， 以及骨质疏松症的危机改善MRONJ的预防、诊断和治疗， 对骨骼疾病患者的保健有很大影响。从父母资助的研究中，我们的 完善的，跨学科的临床医生科学家团队作出了重要贡献， MRONJ的病理生理学、诊断和管理。总的来说，我们的研究提供了重要的 了解MRONJ发病机制。在患有牙病的对照动物中， 炎性病灶相比之下，破骨细胞抑制导致骨暴露于炎症，并导致骨坏死。 邻近炎性病灶的骨坏死。对照组和抗吸收组均发生上皮迁移 对待动物。然而，随着骨吸收的抑制，上皮向牙槽骨下降， 嵴，并最终环绕坏死骨，导致骨暴露。拔牙术用牙科 疾病，导致明显的MRONJ。相比之下，在拔出动物的健康牙齿后， 抗再吸收剂实现粘膜和牙槽愈合。通过我们的研究， 通过诱导实验性牙周病或根尖周病来表征MRONJ的动物模型， 在没有拔牙的情况下，用高剂量的抗吸收药治疗。这些模型捕捉早期组织 MRONJ启动期间的变化。根据我们发表的初步研究结果，我们假设， 最终导致临床骨暴露的病理生理框架的启动涉及 死亡的骨细胞之间的相互作用，挑战软组织稳态，以及扭曲的免疫反应。我们 目的是确定MRONJ发生和进展的早期病理生理机制， 采取有效的治疗措施。为了达到我们的目标和测试我们的假设，我们提出了三个 具体目标。目的1：确定从坏死骨细胞释放的HMGB 1在多大程度上促进了骨形成。 MRONJ启动和进展目标2：描述巨噬细胞参与MRONJ启动和进展 进展目的3：明确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。