Pathophysiologic mechanisms of biosphosphonate related osteonecrosis of the jaws

生物膦酸盐相关颌骨骨坏死的病理生理机制

• 批准号: 8128096
• 负责人: Tara L Aghaloo
• 金额: $ 6.61万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8128096
• 关键词: 8-hydroxy-2' -deoxyguanosine; Abbreviations; Abscess; Acetylcysteine; Address; Affect; Alkaline Phosphatase; Alveolar; Alveolus; Anatomy; Angiogenesis Inhibition; Animal Disease Models; Animal Model; Animals; Antioxidants; Apoptosis; Appearance; Area; Bacterial Infections; Bone Density; Bone Marrow; Bone Resorption; Bone necrosis; Bone remodeling; C-terminal; Cancer Patient; Cell Culture Techniques; Cell Differentiation process; Cell Separation; Cell physiology; Cells; Collagen Type I; Complication; DNA Nucleotidylexotransferase; DSPP gene; Data; Dental Enamel; Development; Dexamethasone; Diagnostic; Diffuse; Disease; Drug usage; Environment; Etiology; Exhibits; Experimental Models; Fistula; Fracture; Frequencies; Functional disorder; Glutathione Disulfide; Hematoxylin and Eosin Staining Method; Histologic; Histopathology; Homeostasis; Human; Hypercalcemia of Malignancy; In Situ Nick-End Labeling; Incidence; Induction of Apoptosis; Infection; Inflammation; Inflammatory; Irregular Bone; Jaw; Jaw Fractures; Label; Laboratories; Lead; Ligands; Lipopolysaccharides; Macrophage Colony-Stimulating Factor; Malignant Bone Neoplasm; Mandible; Marrow; Mediating; Messenger RNA; Metastatic Neoplasm to the Bone; Methods; Modeling; Molecular; Mus; Muscle; Necrosis; Nodule; Oral; Oral cavity; Oral mucous membrane structure; Organ; Osteocytes; Osteomyelitis; Osteoporosis; Osteoradionecrosis; Oxidative Stress; Pain; Pathology; Patients; Periodontal Diseases; Pharmaceutical Preparations; Phenotype; Predisposition; Process; Protocols documentation; Public Health; Publishing; Quality of life; Radiation therapy; Rattus; Reactive Oxygen Species; Recording of previous events; Reduced Glutathione; Reporting; Research; Resistance; Risk; Rodent Model; Role; Series; Severities; Site; Skeleton; Stromal Cells; Superoxide Dismutase; Swelling; TNFSF11 gene; Tartrates; Testing; Time; Tolonium chloride; Tooth Cervix; Tooth Diseases; Tooth structure; Treatment Protocols; Tumor necrosis factor receptor 11b; Vascular Endothelial Growth Factors; Withdrawal; X-Ray Computed Tomography; Xanthine Oxidase; Xanthines; Zoledronate; Zoledronic Acid; alveolar bone; base; bisphosphonate; bone; bone cell; bone healing; craniofacial; crosslink; diacetyldichlorofluorescein; improved; in vitro Model; in vivo; intraperitoneal; long bone; maxillofacial; novel therapeutic intervention; osteoblast differentiation; osteoclastogenesis; perhydroxyl radical; public health relevance; receptor; response; skeletal

DESCRIPTION (provided by applicant): Bisphosphonates (BPs) are commonly used medications to treat primary and metastatic bone cancer, as well as osteoporosis. Though BPs improve bone mineral density, reduce fracture risk, and reduce hypercalcemia of malignancy, many patients develop osteonecrosis of the jaws. BP related osteonecrosis of the jaws (BRONJ) is a devastating complication, presenting as clinically exposed bone in the maxillofacial region for more than 8 weeks. BRONJ is associated with severe pain, swelling, infection, fistulae, and jaw fracture, all of which significantly impact patients' quality of life. Despite the increasing number of BRONJ cases since the first report in 2003, the pathophysiology of the disease remains largely unknown. Two major impediments in exploring BRONJ etiology exist. First, many of our assumptions concerning alveolar bone (AB) cell function and differentiation are extrapolated from experimental models using cells from other skeletal sites. Second, there is no well-established BRONJ animal model to study the in vivo parameters of disease initiation and progression. In this application, we have addressed these two gaps. We have established a method for isolating AB marrow stromal cells (MSCs) and have demonstrated differences in the osteoblastic potential of AB vs. long bone (LB) MSCs, providing a relevant in vitro model to study differences between the craniofacial and appendicular skeleton. Moreover, AB MSCs express lower RANKL mRNA levels and are more sensitive to oxidative stress than their LB counterparts. Published studies and our own preliminary data demonstrate a significant role for dental disease in the pathophysiology of BRONJ. Excitingly, we have developed a rodent model of BRONJ. Equipped both with a model to study AB MSC differentiation in culture and with a BRONJ animal model, our objective is to explore molecular and cellular mechanisms of BRONJ. Based on our preliminary data, we hypothesize that BPs robustly suppress AB resorption at the area of periodontal inflammation. The high oxidative stress environment around the inflammatory nidus strongly decreases AB healing capacity and increases cell apoptosis. The net result of these processes is AB necrosis that presents clinically as BRONJ. To achieve our objective and test our hypothesis, we propose three specific aims: (1) To explore the necessary and sufficient requirement of bisphosphonate treatment and periodontal disease for BRONJ development in the rat; (2) To investigate the ability of AB vs. LB marrow to support osteoclastogenesis in the presence or absence of bisphosphonates; and (3) To investigate the AB vs. LB MSC sensitivity to oxidative stress in the presence or absence of bisphosphonates. The proposed studies will begin uncovering the mechanisms underlying BRONJ pathophysiology and will provide evidence for BP and dental disease involvement in BRONJ incidence. Understanding the mechanisms by which the oral environment is sensitive to oxidative stress and BP inhibition of bone remodeling may lead to novel therapeutic approaches to reduce BRONJ frequency, progression, and severity. PUBLIC HEALTH RELEVANCE: Bisphosphonates are drugs used to treat bone metastasis in cancer patients and osteoporosis. However, bisphosphonate use has been associated with significant oral complications including exposure of the jaw bone, abscesses and jaw fractures. No treatment for these complications exists, because we do not understand the mechanisms of their development. In this application, we explore mechanisms of bisphosphonate related jaw necrosis and establish an animal model of the disease. Results of this research can potentially lead to novel therapeutic approaches that can reduce the incidence, severity, and progression of BRONJ.

描述（由申请人提供）：双膦酸盐（BP）是治疗原发性和转移性骨癌以及骨质疏松症的常用药物。尽管 BP 可以改善骨矿物质密度、降低骨折风险并减少恶性肿瘤引起的高钙血症，但许多患者会出现颌骨坏死。 BP 相关颌骨坏死 (BRONJ) 是一种破坏性并发症，临床上表现为颌面部骨暴露超过 8 周。 BRONJ 与严重疼痛、肿胀、感染、瘘管和颌骨骨折有关，所有这些都会严重影响患者的生活质量。尽管自 2003 年首次报告以来 BRONJ 病例数量不断增加，但该疾病的病理生理学仍然很大程度上未知。探索 BRONJ 病因存在两个主要障碍。首先，我们关于牙槽骨（AB）细胞功能和分化的许多假设都是从使用来自其他骨骼部位的细胞的实验模型推断出来的。其次，没有完善的 BRONJ 动物模型来研究疾病发生和进展的体内参数。在此应用程序中，我们解决了这两个差距。我们建立了一种分离 AB 骨髓基质细胞 (MSC) 的方法，并证明了 AB 与长骨 (LB) MSC 的成骨细胞潜力的差异，为研究颅面和四肢骨骼之间的差异提供了相关的体外模型。此外，与 LB MSC 相比，AB MSC 表达较低的 RANKL mRNA 水平，并且对氧化应激更敏感。已发表的研究和我们自己的初步数据表明，牙科疾病在 BRONJ 的病理生理学中发挥着重要作用。令人兴奋的是，我们开发了 BRONJ 啮齿动物模型。我们配备了研究 AB MSC 培养分化的模型和 BRONJ 动物模型，我们的目标是探索 BRONJ 的分子和细胞机制。根据我们的初步数据，我们假设 BP 可以强有力地抑制牙周炎症区域的 AB 吸收。炎症病灶周围的高氧化应激环境强烈降低AB愈合能力并增加细胞凋亡。这些过程的最终结果是 AB 坏死，临床上表现为 BRONJ。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：（1）探索双膦酸盐治疗和牙周病对大鼠BRONJ发育的充分必要条件； (2) 研究在存在或不存在双膦酸盐的情况下AB与LB骨髓支持破骨细胞生成的能力； (3) 研究在存在或不存在双膦酸盐的情况下AB与LB MSC对氧化应激的敏感性。拟议的研究将开始揭示 BRONJ 病理生理学的潜在机制，并将为 BP 和牙科疾病参与 BRONJ 发病提供证据。了解口腔环境对氧化应激和骨重塑的血压抑制敏感的机制可能会导致新的治疗方法来减少 BRONJ 频率、进展和严重程度。公众健康相关性：双膦酸盐是用于治疗癌症患者骨转移和骨质疏松症的药物。然而，双膦酸盐的使用与严重的口腔并发症有关，包括颌骨暴露、脓肿和颌骨骨折。这些并发症尚无治疗方法，因为我们不了解其发展机制。在本申请中，我们探讨了双膦酸盐相关颌骨坏死的机制并建立了该疾病的动物模型。这项研究的结果可能会带来新的治疗方法，从而降低 BRONJ 的发病率、严重程度和进展。