Role of oral mucosa in bisphosphonate related osteonecrosis of the jaw

口腔粘膜在双膦酸盐相关颌骨坏死中的作用

• 批准号: 7977957
• 负责人: Reuben Han-Kyu Kim
• 金额: $ 11.55万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7977957
• 关键词: 3-Dimensional; Adverse effects; Affect; Animal Model; Apoptosis; Area; Autophagocytosis; Binding; Body part; Bone Diseases; Bone necrosis; Bone remodeling; Cell Culture Techniques; Cells; Clinical; Complex; Data; Dental; Effectiveness; Environment; Enzymes; Etiology; Fibroblasts; Functional disorder; Future; Goals; Grant; Healed; Human; Impaired wound healing; In Vitro; Intervention; Jaw; Lead; Medical; Modality; Modeling; Molecular; Monomeric GTP-Binding Proteins; Necrosis; Nitrogen; Operative Surgical Procedures; Oral; Oral cavity; Oral mucous membrane structure; Osteoclasts; Osteoporosis; Outcome; Pathway interactions; Pattern; Phase; Prevention; Process; Proteins; Role; Severities; Site; Staining method; Surface; Testing; Tooth Extraction; Wound Healing; base; bisphosphonate; bone; cell type; clinical application; farnesyl pyrophosphate; healing; high risk; improved; in vivo; keratinocyte; mevalonate; migration; mutant; oral behavior; overexpression; premature; public health relevance; senescence; wound

DESCRIPTION (provided by applicant): Bisphosphonate (BPs) are potent anti-resorptive agents that are widely used to treat osteoporosis and metastatic bone diseases. Long-term users of BPs are at the higher risk of developing osteonecrosis of the jaw (ONJ). The etiology of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is thought to be due to its inhibitory effects on osteoclasts, bone resorbing cells important for bone remodeling and healing. However, this alone is insufficient to explain the pathophysiology of BRONJ because wound healing in oral environment is a multi-factorial and complex process that requires orchestrated efforts of different cell types including oral mucosal cells. BRONJ commonly occurs at the site of previous tooth extraction or other surgical interventions and is clinically defined as exposed necrotic bone with unhealed and open oral mucosa. Nonetheless, the exact role of oral mucosa in the pathophysiology of BRONJ is not fully understood. To better understand effects of BPs on oral mucosal cells, we established a 3 dimensional (3D) oral mucosal wound healing model and found that BPs drastically inhibit proliferation and migration of keratinocytes. Similar to this ex vivo model, our in vitro studies also showed the marked inhibition of proliferation and migration by BPs specific to primary normal human oral keratinocytes (NHOK). Our recently developed animal model which recapitulates BA-ONJ also revealed the impaired wound closure with underlying exposed and necrotic bone. Based on our preliminary data, we hypothesize that BP directly impairs reepithelialization (e.g., proliferation and migration) of oral mucosa by targeting the mevalonate pathway. To this end, we propose 1) to examine roles of farnesyl pyrophosphate synthase (FPPS) and RhoA in BP-treated NHOK in vitro and ex vivo, and 2) to examine spatial expression patterns of wound healing-associated proteins in vivo using animal model. The clinical outcomes and benefits outweigh the adverse effects of using BPs. Therefore, BPs will continually be used to manage osteoporosis and metastatic bone diseases, and proper treatment and prevention of BRONJ will remain important and relevant clinical issues in dental and medical practices. Our proposal will provide possible explanations as to why BRONJ occurs in oral-cavity specific manner, and will establish a basis for the future clinical applications in managing and treating BRONJ. Successful completions of the current project will likely lead to R01 grant mechanism focusing on the application of findings to the clinical settings. PUBLIC HEALTH RELEVANCE: With the increasing use of bisphosphonates due to its effectiveness in multiple clinical settings, bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been surfaced as a significant dental and medical problem because no definitive prevention and treatment are currently available. Although BRONJ is clinically defined as exposed bone with unhealed and opened overlaying oral mucosa, the exact role of oral mucosa in the pathophysiology of BRONJ is not fully understood. In this proposal, we will investigate direct effects of bisphosphonates on the oral mucosal cells, and our results are expected to contribute significantly on managing long-term bisphosphonate users by improving treatment and prevention modalities.

描述（由申请人提供）：双膦酸盐（BP）是有效的抗骨吸收剂，广泛用于治疗骨质疏松症和转移性骨疾病。长期使用BP的人患颌骨骨坏死（ONJ）的风险更高。双膦酸盐相关性颌骨骨坏死（BRONJ）的病因被认为是由于其对破骨细胞的抑制作用，破骨细胞是骨重建和愈合的重要骨吸收细胞。然而，这本身不足以解释BRONJ的病理生理学，因为口腔环境中的伤口愈合是一个多因素和复杂的过程，需要不同细胞类型（包括口腔粘膜细胞）的协调努力。BRONJ通常发生在先前拔牙或其他手术干预的部位，临床上定义为暴露的坏死骨与未愈合和开放的口腔粘膜。尽管如此，口腔粘膜在BRONJ病理生理学中的确切作用尚未完全了解。为了更好地了解BPs对口腔粘膜细胞的影响，我们建立了一个三维（3D）口腔粘膜伤口愈合模型，发现BPs显著抑制角质形成细胞的增殖和迁移。与该离体模型相似，我们的体外研究也显示了对原代正常人口腔角质形成细胞（NHOK）特异性的BP对增殖和迁移的显著抑制。我们最近开发的动物模型概括了BA-ONJ，也显示了受损的伤口闭合以及潜在的暴露和坏死骨。基于我们的初步数据，我们假设BP直接损害上皮再生（例如，增殖和迁移）。为此，我们建议1）检查法尼基焦磷酸合酶（FPPS）和RhoA在BP处理的NHOK中的作用，在体外和离体，和2）使用动物模型检查体内伤口愈合相关蛋白的空间表达模式。临床结局和受益超过使用BP的不良反应。因此，BP将继续用于管理骨质疏松症和转移性骨疾病，BRONJ的适当治疗和预防将仍然是牙科和医疗实践中重要和相关的临床问题。我们的建议将提供可能的解释，为什么BRONJ发生在口腔特异性的方式，并将建立一个基础，为未来的临床应用在管理和治疗BRONJ。当前项目的成功完成可能会导致R 01赠款机制，重点是将研究结果应用于临床环境。 公共卫生关系：由于双膦酸盐在多种临床环境中的有效性，随着双膦酸盐的使用越来越多，双膦酸盐相关的颌骨骨坏死（BRONJ）已成为一个重要的牙科和医学问题，因为目前没有明确的预防和治疗方法。虽然BRONJ在临床上被定义为暴露的骨与未愈合和开放的覆盖口腔粘膜，口腔粘膜在BRONJ的病理生理学中的确切作用尚未完全了解。在这项提案中，我们将研究双膦酸盐对口腔粘膜细胞的直接影响，我们的研究结果有望通过改善治疗和预防方式，对管理长期双膦酸盐使用者做出重大贡献。