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: 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
• 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

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.

抗吸收药物，特别是双磷酸盐(BPS)和地诺单抗是有效的抑制 破骨细胞功能，用于治疗骨骼疾病，如骨恶性肿瘤或骨质疏松症。 虽然这些药物在临床上很重要，但与药物相关的骨坏死有关。 颌骨(MRONJ)，一种罕见但严重的副作用，可导致虚弱的疼痛和发病率。此外，恐惧 MRONJ的发展导致患者对抗吸收药物的依从性逐渐下降， 以及迫在眉睫的骨质疏松症危机。改进MRONJ的预防、诊断和治疗将产生 对骨骼疾病患者的医疗保健影响很大。由家长资助的研究，我们的 由临床医生和科学家组成的成熟的跨学科团队为 MRONJ的病理生理、诊断和治疗。总体而言，我们的研究提供了重要的 对MRONJ发病机制的洞察。在患有牙病的对照动物中，骨骼从 炎性结节。相比之下，破骨细胞抑制会导致骨骼暴露在炎症中，并 炎性病灶附近的骨坏死。上皮迁移在对照组和抗吸收组均可发生 治疗过的动物。然而，随着骨吸收的抑制，上皮向牙槽方向下降。 最后形成坏死骨的边缘，导致骨骼外露。牙科拔牙术 疾病，导致明显的MRONJ。相比之下，在动物的健康牙齿拔除后 抗吸收药，粘膜和牙槽愈合。通过我们的学习，我们开发了和 通过诱导实验性牙周或根尖周病来表征MRONJ动物模型 在不拔牙的情况下，使用大剂量的抗吸收药物治疗。这些模型捕捉早期组织 MRONJ启动期间的变化。根据我们公布的和初步的发现，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到 死亡的骨细胞之间的相互作用，软组织动态平衡受到挑战，以及扭曲的免疫反应。我们的 目的探讨MRONJ发生和发展的早期病理生理机制及临床意义。 寻求有效的治疗干预措施。为了达到我们的目标并检验我们的假设，我们提出了三个 明确的目标。目标1：确定从坏死骨细胞释放的HMGB1在多大程度上有助于 MRONJ的启动和进展目标2：描绘巨噬细胞参与MRONJ的启动和进展 进步。目的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 开始和进展。