Integrating craniofacial morphology, oral function, temporomandibular biomechanics and mechanobiology to determine sex-specific TMJ pathophysiology in humans

项目摘要 在美国，约有3500万人受到颞下颌关节紊乱病的影响，其中受影响的女性是 男人。大约30%的颞下颌关节紊乱症患者经历了关节的机械功能障碍 颞下颌关节(TMJ)中的关节盘(一种无血管组织)，是口腔功能过程中的承重关节。 然而，关于颞下颌关节盘功能障碍/移位(TMDD)亚群的病因学研究很少。 理解，包括为什么女性受到不成比例的影响。逻辑TMDD候选生物指示器 包括颅面形态、TMJ生物力学、关节盘营养物质利用率和关节盘新陈代谢 表现出不同程度的性二形性。这些因素相互作用，使得特定受试者的头面部 形态驱动TMJ的生物力学，生物力学调节TMJ的营养物质供应和细胞 新陈代谢/内稳态。之前R01的研究结果证明，在猪的无血管TMJ盘 养分环境严重依赖于机械应变依赖的养分扩散，而养分 环境对椎间盘细胞的增殖和分化有深刻的影响，导致组织功能障碍。 因此，颅面驱动的TMJ生物力学和力学生物学存在性别差异。 人类的形态可能是至关重要的。我们的初步数据显示了人类TMJ的性别差异 由于颅面形态中的性别二态所致的负荷，加上我们已经确定了TMJ的形态 表型也可以解释TMDD发生的性别差异。因此，现在有必要 确定依赖机械应变的养分运输特性和营养水平的性别差异- 人TMJ间盘的能量依赖代谢及其与颅面的可能联系 TMDD发生和发展过程中的形态和TMJ生物力学 进步。这项研究的中心假设是颅面形态的差异 性别以及健康对照组和TMDD患者之间的差异是导致TMJ生物力学和TMJ差异的原因 椎间盘机械生物学，可用于预测患TMDD风险最高的个体和 进步。长期目标是了解颞下颌关节的机械生物学病因。 疾病，确定TMDD发生的特定危险因素，并确定TMDD的机制生物学 进程的机制。通过鉴定潜在的形态、生物力学和生物学 TMDD发生和发展的危险因素，这项工作具有良好的临床应用前景，并奠定了 为未来的人类研究奠定了基础。拟议研究的具体成果包括：确定 颞下颌关节盘营养环境的机械应变依赖性及其对细胞活力的影响 和人体组织中的能量代谢，增强了对受试者特定形态如何 结果不同受试者在颞下颌关节生物力学上的差异，以及TMDD特异性的鉴定 机械生物学生物指示器。

Project Summary Temporomandibular disorders affect ~35 million people in the US, with 3-8 times more women affected than men. Approximately 30% of temporomandibular disorder patients experience mechanical dysfunction of the articular disc (an avascular tissue) in the temporomandibular joint (TMJ), a load-bearing joint during oral function. However, the etiology of the temporomandibular disc dysfunction/displacement (TMDD) sub-population is poorly understood, including why women are disproportionately affected. Logical TMDD candidate bio-indicators include craniofacial morphology, TMJ biomechanics, disc nutrient availability, and disc metabolism, each of which show varying degrees of sexual dimorphism. These factors interact such that subject-specific craniofacial morphology drives TMJ biomechanics, and biomechanics regulates TMJ disc nutrient availability and cellular metabolism/homeostasis. Study results from the preceding R01 proved that in pigs the avascular TMJ disc nutrient environment is heavily dependent upon mechanical strain-dependent nutrient diffusion, and the nutrient environment has a profound effect on disc cell proliferation and differentiation leading to tissue dysfunction. Therefore, TMJ biomechanical and mechanobiological differences between sexes driven by craniofacial morphology in humans may be critical. Our preliminary data have demonstrated sex-differences in human TMJ loading due to sexual dimorphisms in craniofacial morphology, plus we have identified a TMJ morphologic phenotype that may also explain sex-differences in TMDD occurrence. Therefore, it is now necessary to determine sex differences in the mechanical strain-dependent nutrient transport properties and nutrient level- dependent energy metabolism of the human TMJ disc and investigate the plausible associations of craniofacial morphology and TMJ biomechanics through the mechanobiological pathway on TMDD development and progression. The central hypothesis of the proposed study is that craniofacial morphologic differences between sexes, as well as between healthy controls and TMDD patients, drive the differences of TMJ biomechanics and disc mechanobiology which can be used to predict individuals at greatest risk for TMDD development and progression. The long-term objectives are to understand the mechanobiological etiology of temporomandibular disorders, to identify risk factors specific for TMDD development, and to define TMDD mechanobiological mechanisms of progression. Through the identification of potential morphologic, biomechanical, and biological risk factors for TMDD development and progression, this work has promising clinical translation and lays the foundation for future human studies. Specific outcomes of the proposed study include: determination of the mechanical strain dependency of the temporomandibular disc nutrient environment and its impact on cell viability and energy metabolism in human tissues, an enhanced understanding of how subject-specific morphology results in subject-specific differences in temporomandibular biomechanics, and identification of TMDD-specific mechanobiological bio-indicators.