Role of Estrogen via Estrogen Receptor Alpha on TMJ Chondrogenesis and Homeostasis

项目摘要 大多数美国人患有颞下颌关节退行性变和 骨性关节炎(TMJ-OA)是年龄在45岁到65岁之间的女性。TMJ-OA在该人群中的患病率 提示雌激素丢失在该病的发病机制中起一定作用。我们实验室之前的证据表明 雌激素通过雌激素受体α(ER-α)，通过促进COL_2和COL_2，保护TMJ免于退变 蛋白质多聚糖生产。此外，我们有初步证据表明，雌激素-ERα抑制WNT 通路信号。这些发现表明雌激素信号通过ERα促进软骨形成。 调节典型的Wnt途径。这项建议的目的是研究ERα的作用 下颌突软骨基质生成和TMJ动态平衡的信号转导。 拟议的工作包括两个目标： 目的1：探讨雌激素通过内质网α对II型胶原(COL2)产生的影响。我们假设 雌激素通过抑制典型的Wnt信号，通过ERα促进COL2的转录。以确认效果 关于雌激素-ERα对软骨形成的影响，报告鼠将被用于检测COL2和COL2的上调 雌激素和ERα激动剂下调Wnt信号。那么，雌激素-ERα促进的能力 通过激活WT和ERαKO中的Wnt信号通路来确定抑制Wnt信号的软骨形成 卵巢切除-雌激素替代模型中的小鼠。 目的2：确定内质网α缺乏对颞下颌关节退变的影响及其与结果的相关性 压缩性能和咀嚼功能。我们假设ERαKO小鼠将表现出加速 与年龄相关的TMJ退变，将对应于固定电荷压缩模数的下降 密度和咬合力与WT对照组进行比较。基质成分的变化将与变化相关 在压缩性能和咀嚼功能方面。 这项拟议研究的结果将为TMJ变性和性倾向提供证据 提供治疗靶点(如ERα激动剂)以延缓退变。 通过这项工作，我们旨在加深对雌激素在TMJ关节软骨中的作用的了解 软骨生成和动态平衡。此外，TMJ关节软骨结构/功能的研究进展 关系将有利于开发抗击TMJ的再生疗法 退化。

Project Summary The majority of the US population that suffers from temporomandibular joint (TMJ) degeneration and osteoarthritis (TMJ-OA) are females between 45 and 65 years old. Prevalence of TMJ-OA in this population suggests that estrogen loss plays a role in the disease pathogenesis. Previous evidence from our lab suggests that estrogen through estrogen receptor alpha (ERα) protects the TMJ from degeneration by promoting Col2 and proteoglycan production. Further, we have preliminary evidence indicating that estrogen-ERα inhibits Wnt pathway signaling. These findings suggest that estrogen signaling promotes chondrogenesis via ERα by mediating the canonical Wnt pathway. The objective of this proposal is to investigate the role of ERα signaling on mandibular condylar cartilage matrix production and TMJ homeostasis. The proposed work comprises two aims: AIM 1: Evaluate the role of estrogen via ERα on collagen type II (Col2) production. We hypothesize that estrogen promotes Col2 transcription via ERα by inhibiting canonical Wnt signaling. To confirm the effects of estrogen-ERα on chondrogenesis, reporter mice will be utilized to examine upregulation of Col2 and downregulation of Wnt signaling with estrogen and an ERα agonist. Then, the ability of estrogen-ERα to promote chondrogenesis by inhibiting Wnt signaling will be determined by activating the Wnt pathway in WT and ERαKO mice in an ovariectomy-estrogen replacement model. AIM 2: Determine the effects of ERα deficiency on TMJ degeneration and correlate to resulting compressive properties and masticatory function. We hypothesize that ERαKO mice will exhibit accelerated age-related TMJ degeneration which will correspond to a decrease in compressive modulus, fixed charge density, and bite force compared to WT controls. Changes in matrix composition will be correlated to alterations in compressive properties and masticatory function. The results from this proposed research will provide evidence of the sex predilection of TMJ degeneration and provide therapeutic targets (e.g. ERα agonist) to delay degeneration. Through this work, we aim to enhance the understanding of estrogen’s role in TMJ condylar cartilage chondrogenesis and homeostasis. Also, the development of TMJ condylar cartilage structure/function relationships will be beneficial for the development of regenerative therapies to combat TMJ degeneration.