Chondrocyte-pericellular matrix derived signaling maintains tissue integrity in the temporomandibular joint

软骨细胞-细胞周基质衍生的信号传导维持颞下颌关节的组织完整性

基本信息

批准号：
9762079
负责人：
David Andrew Reed
金额：
$ 15.99万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9762079
关键词：
Affect Animal Model Anoikis Antigens Apoptotic Attenuated Autophagocytosis Binding Biology Cartilage Cartilage Matrix Cell Death Cell Nucleus Cell Proliferation Cells Cellular Stress Chondrocytes Classification Clinical Clinical Pathology Collagen Type VI Cytosol Data Degenerative polyarthritis Disease Etiology Foundations Functional disorder GRP78 gene Genetic Transcription Goals Growth HTRA2 gene Health Homeostasis Human In Vitro Inflammatory Intervention Intervention Studies Knock-out Knockout Mice Link Mandible Measures Mechanical Stress Mechanics Mediating Mediator of activation protein Metabolic Metabolic stress Methods Molecular Molecular Target Nerve Nuclear Translocation Operative Surgical Procedures Oxidative Stress Pathway interactions Patients Peptide Hydrolases Population Prevention Proteolysis Regulation Research Role Signal Transduction Stress Structure Synovial Fluid Temporomandibular Joint Temporomandibular Joint Disorders Testing Therapeutic Time Tissue Engineering Tissues Transgenic Organisms Translational Research Treatment Efficacy Wound Healing articular cartilage biological adaptation to stress cartilage degradation cell type condylar cartilage endoplasmic reticulum stress experimental study interdisciplinary collaboration interest migration mouse model nerve agent novel pre-clinical programs receptor repaired response success therapeutic target translational pipeline

项目摘要

ABSTRACT Chondrocyte-pericellular matrix derived signaling maintains tissue integrity in the temporomandibular joint Temporomandibular disorders affect 3-7% of the population. TMJ condylar cartilage integrity is central to TMJ health and many TMDs are associated with its degeneration. The pathophysiology of degenerative joint disease (DJD) in the TMJ is ill-defined and contemporary molecular targets for clinical intervention have yet to be determined. Chondrocyte-pericellular matrix derived signaling is a known regulator of cartilage homeostasis and it represents a promising potential therapeutic target for DJD. The major component of the pericellular matrix in the TMJ is type VI collagen. Nerve/glial antigen 2 (NG2) is a known receptor of type VI collagen, but NG2-type VI collagen interactions have not been studied in detail in mandibular condylar cartilage. In other cell types, the NG2-pericellular matrix interactions are a critical regulator of cell proliferation, differentiation, migration, and viability. Our preliminary data illustrate that a) NG2 colocalizes with type VI collagen in healthy articular chondrocytes in the TMJ, b) that this colocalization is disrupted during degeneration, c) that degenerative changes are associated with high levels of internalized NG2, d) and that internalized NG2 is closely associated with a marker for oxidative stress, OMI/HtrA2. We hypothesize that cartilage degeneration in TMJ DJD is mediated, in part, by proteolytic cleavage of the NG2 ectodomain, activation, and internalization to regulate oxidative stress through OMI/Htra2 pathway. We will test this hypothesis with two specific aims. In aim 1, we will implicate ectodomain proteolysis in NG2 activation and internalization by linking cartilage degeneration with NG2 internalization and measured protease levels in wild-type and protease knockout mice and cells. In aim 2, we will define the functionality of NG2 as a mediator of oxidative stress by linking cartilage degeneration with markers of oxidative stress, ER stress, and autophagy in wild-type and NG2 knockout mice and cells. Together, these aims define and evaluate an entirely novel molecular mechanism of chondrocyte function that is contextually linked to mechanical and metabolic oxidative stresses known to cause TMDs. Long term, we seek to use these data to solve clinical problems associated with defining precise methods of TMD classification, prevention, and treatment.

抽象的软骨细胞 - 细胞基质衍生的信号传导保持颞下颌的组织完整性联合的颞下颌疾病会影响3-7％的人口。 TMJ Condylar软骨完整性是TMJ的核心健康和许多TMD与其变性有关。退化关节的病理生理 TMJ中的疾病（DJD）是不确定的，当代的临床干预分子靶标尚未可以确定。软骨细胞 - 细胞基质衍生信号传导是软骨稳态的已知调节剂它代表了DJD的有希望的潜在治疗靶点。细胞周围的主要组成部分 TMJ中的矩阵是VI型胶原蛋白。神经/神经胶质抗原2（NG2）是VI型胶原蛋白的已知受体，但 NG2型VI胶原蛋白相互作用尚未在下颌骨软骨中进行详细研究。在其他单元格中类型，NG2-细胞基质相互作用是细胞增殖，分化，迁移和生存能力。我们的初步数据表明，a）NG2与健康中的VI型胶原蛋白共定位 TMJ中的关节软骨细胞，b）这种共定位在变性过程中被破坏，c）退化性变化与高水平的内在ng2，d）有关，并且内部化的NG2为与氧化应激的标记密切相关，OMI/HTRA2。我们假设软骨变性在TMJ中，DJD部分是由NG2外域的蛋白水解切割介导的，激活和内在化介导通过OMI/HTRA2途径调节氧化应激。我们将以两个具体的目的检验这一假设。在 AIM 1，我们将通过连接软骨将胞外域蛋白水解在NG2激活和内在化中牵连野生型和蛋白酶基因敲除小鼠的NG2内在化和测量的蛋白酶水平的变性和细胞。在AIM 2中，我们将通过连接软骨来将NG2的功能定义为氧化应激的介体野生型和NG2敲除小鼠的氧化应激，ER应力和自噬的标记变性和细胞。这些目的共同定义和评估了软骨细胞的完全新颖的分子机制与已知引起TMD的机械和代谢氧化应激相关的功能。长的术语，我们寻求使用这些数据来解决与定义TMD精确方法相关的临床问题分类，预防和治疗。