Understanding the mechanism of radiotherapy-induced dentition breakdown

全世界每年有近40万例口腔癌被诊断出来。大多数人接受放射治疗， 这挽救了病人的生命，但会导致辐射引起的并发症，如口干症，严重的 牙列破裂和咀嚼功能丧失。对放射治疗后牙列的认识现状 崩溃，辐射引起的口干症被认为是最重要的病因，但不 充分解释观察到的辐射后损伤的特征，包括负载时的初始牙釉质损失和 屈曲部位(颈部/切骨/牙尖)。我们最近的临床研究数据首次表明， 牙齿水平辐射剂量和个别牙齿损伤的严重程度之间的独立联系。因此，未来 预防和治疗放射治疗后牙列破裂的改进取决于对 辐射致牙齿损伤的潜在机制。一种解释辐射诱发的机制 牙齿水平的细分目前尚不清楚。一种可能的解释可能与体外试验的报道有关 辐射引起的牙釉质和牙本质物理性质的改变。然而，牙列崩溃 放射治疗后往往在第一年内开始，并随着时间的推移变得更加严重。我们建议 辐射可能会导致牙齿结构的直接变化，但也必须考虑其他因素才能 解释从放射治疗到牙列崩溃所经过的时间。一个重要的促成因素 可能是周期性咬合负荷。我们预计放射治疗对牙齿结构的影响会变得更大 随着时间的推移，明显具有咀嚼功能。另一个机制因素可能是辐射诱导的激活 牙本质小管和胶原基质中的基质金属蛋白酶(MMPs)。基质金属蛋白酶激活 随之而来的胶原蛋白降解可能会导致性质和结构的变化，这也部分解释了 流逝的时间。我们的中心假设是放射治疗可以直接引起胶原蛋白和 牙齿相关MMPs引导活性增加的矿物质结构和可能的间接变化 导致额外的胶原基质降解。累积起来，这些影响可能会导致属性/结构的变化 牙本质、牙釉质和DEJ的分布会对功能状态下的应力分布产生不利影响 正在装车。具体目的将决定1)放射治疗是否改变牙本质的机械性能， 牙釉质和DEJ；2)机械性能的差异与化学成分有关 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 通过有限元模型预测；5)放射治疗增加牙齿相关酶的活性，如MMPs 导致额外的胶原蛋白降解。建议的研究结果应确定机制(S) 负责放射治疗对牙列的影响和牙列结构/功能特征的改变 辐射牙齿使放射后口腔癌患者的预防性和恢复性治疗得到改善。

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.