Understanding the mechanism of radiotherapy-induced dentition breakdown

描述（由申请人提供）：全世界每年诊断出近40万例口腔癌。大多数采用放射治疗，这可以挽救病人的生命，但会导致放射引起的并发症，如口干、严重牙列破坏和咀嚼功能丧失。目前对辐射后牙列破坏的理解，认为辐射诱导的口干症是最重要的病因，不能充分解释观察到的辐射后损伤特征，即在加载和弯曲部位（颈部/切缘/尖部）出现初始釉质损失。我们最近的临床研究数据首次表明牙齿水平辐射剂量与个体牙齿病变严重程度之间存在直接和独立的联系。因此，未来预防和治疗辐射后牙列破坏的改进取决于对辐射引起的牙齿损伤的潜在机制的新认识。目前尚不清楚解释牙齿水平辐射诱导击穿的机制。一个可能的解释可能与体外辐射引起的牙釉质和牙本质物理性质变化的报告有关。然而，放疗后的牙列破坏往往在第一年内开始，并随着时间的推移变得更加严重。我们认为，辐射可能会导致牙齿结构的直接变化，但其他因素也必须考虑，以解释放疗和牙列崩溃之间的时间。一个重要的影响因素可能是周期性咬合负荷。我们预期放射线治疗对牙齿结构的影响会随着时间的推移而变得更加明显。另一个机制因素可能是辐射诱导的牙本质小管和胶原基质中基质金属蛋白酶（MMPs）的活化。MMP活化后胶原降解可能有助于性质和结构的变化，也部分解释了经过的时间。我们的中心假设是，放疗可能会导致胶原蛋白和矿物质结构的直接变化，并可能通过增加牙齿相关的MMP的活性，导致额外的胶原蛋白基质降解的间接变化。累积起来，这些影响可能导致牙本质、牙釉质和DEJ的性质/结构变化，这将对功能载荷下的应力分布模式产生不利影响。具体目标将确定1）放射治疗是否改变牙本质、釉质和DEJ的机械性质; 2）所得的机械性质差异与化学组成/结构变化相关; 3）咬合/功能负载进一步改变辐射牙齿的机械性质和结构; 4）如有限元建模所预测的，辐射诱导的性质/结构变化对DEJ处的负载转移产生负面影响; 5）放疗增加牙齿相关酶如MMP的活性，导致额外的胶原蛋白降解。拟议的研究结果应确定放射治疗对牙列的影响机制，以及放射牙齿的结构/功能特征改变，从而改善放射治疗后口腔癌患者的预防和修复治疗。 公共卫生相关性：全世界每年诊断出近40万例口腔癌。大多数采用放射治疗，这挽救了患者的生命，但会导致放射引起的并发症，如口干症（口干）、严重的牙列破坏和咀嚼功能丧失。我们最近的临床研究数据首次表明，牙齿水平的辐射剂量与单个牙齿损坏的严重程度之间存在直接和独立的联系。因此，未来预防和治疗辐射后牙列破坏的改进取决于对牙齿水平辐射诱导损伤的潜在机制的新认识。

DESCRIPTION (provided by applicant): Worldwide nearly 400,000 cases of oral cancer are diagnosed annually. Most are treated with radiotherapy, which saves the life of the patient but results in radiation-induced complications such as xerostomia, severe dentition breakdown and loss of masticatory function. The present understanding of post-radiation dentition breakdown, with radiation-induced xerostomia considered the most significant etiological factor, does not adequately explain the observed post-radiation lesion characteristics with initial enamel loss at loading and flexure sites (cervical/incisal/cuspal). Our recent clinical study data indicate for the first time a direct and independent link between tooth-level radiation dose and the severity of the individual tooth lesion. Thus, future improvements for preventing and treating post-radiation dentition breakdown depend on new knowledge of the underlying mechanism of radiation-induced tooth damage. A mechanism explaining radiation-induced breakdown at the tooth level is currently unknown. A potential explanation could be linked to reports of in vitro radiation-induced changes in the physical properties of enamel and dentin. However, dentition breakdown following radiotherapy tends to start within the first year and become more severe with time. We propose that radiation may cause a direct change in tooth structure, but other factors must also be considered in order to explain the elapsed time between radiotherapy and dentition breakdown. One important contributing factor could be cyclic occlusal loading. We expect that effects of radiotherapy on the structure of teeth become more evident with masticatory function over time. Another mechanistic factor could be radiation-induced activation of matrix metalloproteinases (MMPs) in the dentinal tubules as well as the collagen matrix. MMP activation followed by collagen degradation could contribute to property and structure changes and also partially explain the elapsed time. Our central hypothesis is that radiotherapy could cause direct changes in collagen and mineral structures and possible indirect changes through increased activity of tooth-associated MMPs leading to additional collagen matrix degradation. Cumulatively, these effects could result in property/structure changes of dentin, enamel and the DEJ that would adversely affect the stress distribution pattern under functional loading. The specific aims will determine whether 1) radiotherapy changes the mechanical properties of dentin, enamel and the DEJ; 2) resultant mechanical property differences correlate with chemical composition/structure changes; 3) occlusal/functional loading further alters mechanical properties and structure of radiated teeth; 4) radiation-induced property/structure changes negatively affect load transfer at the DEJ as predicted by finite element modeling; 5) radiotherapy increases activity of tooth-associated enzymes like MMPs leading to additional collagen degradation. The proposed study outcomes should identify mechanism(s) responsible for radiotherapy effects on the dentition and the altered structure/function characteristics of radiated teeth leading to improved preventive and restorative treatments for oral cancer patients post-radiation. PUBLIC HEALTH RELEVANCE: Worldwide nearly 400,000 cases of oral cancer are diagnosed annually. Most are treated with radiotherapy, which saves the life of the patient but results in radiation-induced complications such as xerostomia (dry mouth), severe dentition breakdown and loss of masticatory function. Our recent clinical study data indicate for the first time a direct and independent link between tooth-level radiation dose and the severity of the individual tooth breakdown. Thus, future improvements for preventing and treating post-radiation dentition breakdown depend on new knowledge of the underlying mechanism of radiation-induced damage at the tooth level.