内质网应激信号在颞下颌关节盘前移位中的作用及机制研究

The apoptosis and changes of metabolic functions in the chondrocytes are the two important factors that affect the emergence and development of the temporomandibular joint disorders (TMD). As a kind of subcellular level of stress reaction, endoplasmic reticulum stress (ERS) is closely related to the degree of articular cartilage degeneration. It has been reported ERS induces the pathway of apoptosis which plays a significant role in regulating cell apoptosis, differentiation, function as well as inflammatory reaction. In our previous study, we found that the expression of ERS-induced apoptotic molecules, PERK and CHOP, was enhanced along with the intensity of hydrostatic pressures in the mandibular condylar chondrocytes. We are speculating that ERS-induced apoptotic pathway is likely to play an important role in apoptosis and metabolic change of chondrocytes, as well as the pathogenesis of TMD. However, the effect and molecular mechanisms of ERS in the TMD are still unclear. The objectives of this study are to investigate the expression and activation of ERS signal molecules in mechanical and inflammatory induced mandibular condylar chondrocytes and animal models of anterior disc displacement. And, the effect of apoptotic CHOP signal on the function and metabolism of the chondrocytes are further investigated. It may offer useful clues to reveal the relationship between ERS-induced apoptotic signal and the development of TMD. Therefore, this study will not only help deeply understand the pathogenesis of TMD, but also provide new intervening therapies for the prevention and treatment of TMD.

软骨细胞的凋亡及代谢功能改变是颞下颌关节紊乱病(TMD)发生和发展的重要因素。内质网应激(ERS)作为一种亚细胞水平的应激反应，与关节软骨的病变程度密切相关，由其介导的凋亡信号途径在调控软骨细胞凋亡、分化、功能及关节炎症反应中发挥重要作用。前期研究发现，颞下颌关节髁突软骨细胞中ERS凋亡相关分子PERK和CHOP的表达随着应力增大而增强，推测ERS信号及其介导的凋亡信号途径在TMD的发生和发展过程中起重要作用，但其具体的分子机制尚不明确。本研究拟建立体外培养的颞下颌关节髁突软骨细胞和关节盘前移位动物模型，综合分析应力作用和炎症刺激下ERS信号分子在关节软骨中的分布、表达和活化，着重探讨CHOP凋亡信号对软骨细胞凋亡及代谢功能的调控，进而揭示ERS信号及其介导的凋亡途径与TMD发展和转归的联系。本研究将有助于更深入地探讨TMD的发病机制，从而为TMD的防治研究提供新的思路和实验依据。

软骨细胞的凋亡及代谢功能改变是颞下颌关节紊乱病(TMD)发生和发展的重要因素。内质网应激(ERS)作为一种亚细胞水平的应激反应，与关节软骨的病变程度密切相关，由其介导的凋亡信号途径在调控软骨细胞凋亡、分化、功能及关节炎症反应中发挥重要作用。ERS信号通路很可能是影响TMD 病程发展和转归的重要因素。但是目前对ERS 信号及其介导的凋亡途径在TMD 发生和发展中的作用及调控机制仍不清楚。本研究通过建立体外培养的颞下颌关节髁突软骨细胞和关节盘前移位（ADD）动物模型的基础上，分析应力作用下ERS信号分子在关节软骨中的分布、表达和活化，探讨了CHOP凋亡信号对软骨细胞凋亡及代谢功能的调控，进而揭示ERS信号及其介导的凋亡途径与TMD发展和转归的联系。本研究将有助于更深入地探讨TMD的发病机制，为缓解或阻断ADD后髁突软骨病理性改变提供新的策略和实验依据。此外，本研究还通过建立大鼠佐剂性颞下颌骨关节炎（TMJOA）动物模型，明确了hedgehog信号通路中不同的受体和配体在TMJOA发展中表达和调控作用，为进一步阐明颞下颌关节疾病相关软骨退变的分子机制，及临床上更有效地治疗颞下颌关节疾病，研制防治软骨破坏新药物提供实验依据。