Understanding the mechanism of radiotherapy-induced dentition breakdown

全世界每年诊断出近40万例口腔癌。大多数人接受放射治疗， 这挽救了患者的生命，但导致辐射引起的并发症， 牙列破坏和咀嚼功能丧失。放射线照射后牙列的研究现状 辐射引起的口干症被认为是最重要的病因， 充分解释观察到的辐射后损伤特征，在加载时初始釉质损失， 弯曲部位（颈/切/尖）。我们最近的临床研究数据首次表明， 牙齿水平的辐射剂量和个别牙齿病变的严重程度之间的独立联系。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。一种解释辐射诱导的 目前尚不清楚牙齿层面的损坏情况。一个潜在的解释可能与体外研究报告有关。 辐射引起的牙釉质和牙本质物理性质的变化。然而，牙列破裂 放疗后的复发倾向于在第一年内开始，并随着时间的推移变得更加严重。我们建议 辐射可能导致牙齿结构的直接变化，但也必须考虑其他因素， 解释放疗和牙列断裂之间的时间间隔。一个重要的促成因素是 可能是周期性咬合负荷。我们希望放射治疗对牙齿结构的影响越来越大， 随着时间的推移，咀嚼功能明显。另一个机制因素可能是辐射诱导的激活， 基质金属蛋白酶（MMP）在牙本质小管以及胶原基质。MMP活化 其次是胶原蛋白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，放射治疗可能会导致胶原蛋白的直接变化， 矿物结构和可能的间接变化，通过增加活动的牙齿相关的基质金属蛋白酶， 导致胶原蛋白基质进一步降解。累积起来，这些影响可能导致性质/结构变化 牙本质，釉质和DEJ的，这将对应力分布模式的功能下， 加载中具体目标将决定1）放射治疗是否改变牙本质的力学性能， 釉质和DEJ; 2）由此产生的机械性能差异与化学 组成/结构变化; 3）咬合/功能负荷进一步改变机械性能和结构 4）辐射引起的性能/结构变化对DEJ的载荷传递产生负面影响， 通过有限元建模预测; 5）放射治疗增加牙齿相关酶如MMPs的活性 导致额外的胶原降解。拟议的研究成果应确定机制 负责放射治疗对牙列的影响和改变的结构/功能特征， 放射治疗的牙齿，从而改善口腔癌患者放射治疗后的预防和恢复治疗。

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.