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（TMJ）变性， 骨关节炎（TMJ-OA）患者为45至65岁的女性。该人群中TMJ-OA的患病率 提示雌激素丢失在疾病发病机制中起作用。我们实验室之前的证据表明 雌激素通过雌激素受体α（ERα）通过促进Col 2和 蛋白聚糖的产生。此外，我们有初步证据表明雌激素-ER α抑制Wnt 信号通路这些发现表明，雌激素信号通过ERα促进软骨形成， 介导经典Wnt途径。本研究的目的是探讨ERα的作用， 信号传导对下颌髁突软骨基质产生和TMJ稳态的影响。 拟议的工作包括两个目标： 目的1：探讨雌激素通过雌激素受体α（ERα）对II型胶原（Col 2）生成的影响。我们假设 雌激素通过抑制经典的Wnt信号通路，通过ERα促进Col 2的转录。为了确认效果 为了研究雌激素-ER α对软骨形成的影响，报告小鼠将用于检查Col 2的上调， 用雌激素和ERα激动剂下调Wnt信号传导。然后，雌激素-ER α促进 通过抑制Wnt信号传导的软骨形成将通过激活WT和ERαKO中的Wnt通路来确定 卵巢切除-雌激素替代模型中的小鼠。 目的2：探讨雌激素受体α（ERα）缺乏对颞下颌关节退行性变的影响， 压缩性能和咀嚼功能。我们假设ERαKO小鼠将表现出加速的 与年龄相关的TMJ退化，这将对应于压缩模量的降低，固定电荷 密度和咬合力。基质组成的变化将与 压缩性能和咀嚼功能。 这项研究的结果将为颞下颌关节变性的性别偏好提供证据， 提供治疗靶点（如ERα激动剂）以延缓变性。 通过这项工作，我们的目的是加强了解雌激素的作用，颞下颌关节髁突软骨 软骨形成和体内平衡。此外，TMJ髁突软骨结构/功能的发育 这种关系将有利于再生疗法的发展，以打击颞下颌关节 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.