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

• 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
• 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

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.

摘要 软骨细胞-细胞周围基质来源的信号转导维持颞下颌骨的组织完整性 接合 3%-7%的人患有颞下颌关节紊乱病。髁突软骨的完整性是TMJ的核心 健康和许多TMD与其退变有关。退行性关节的病理生理学 TMJ中的疾病(DJD)定义不明确，当代临床干预的分子靶点尚未确定 要下定决心。软骨细胞-细胞周围基质衍生的信号是软骨内稳态的已知调节因素 它是治疗DJD的一个有前景的潜在靶点。细胞周膜的主要成分 TMJ中的基质为VI型胶原。神经胶质抗原2(NG2)是一种已知的VI型胶原受体，但 NG2-VI型胶原在下颌骨髁状突软骨中的相互作用尚未得到详细研究。在其他单元格中 类型，NG2与细胞外基质的相互作用是细胞增殖、分化、 迁徙和生存能力。我们的初步数据表明，在健康人群中，a)NG2与VI型胶原共定位 关节软骨细胞在TMJ，b)这种共定位在退变过程中被破坏，c) 退行性变化与高水平的内在化NG2，d)相关，内在化NG2是 与氧化应激的标志物OMI/HtrA2密切相关。我们假设软骨退变 在TMJ中，DJD部分是通过NG2胞外区的蛋白水解性切割、激活和内化来介导的 通过Omi/Htra2途径调节氧化应激。我们将通过两个具体目标来检验这一假设。在……里面 目的1，我们将通过连接软骨，将胞外结构域蛋白分解与NG2的激活和内化联系起来 野生型和蛋白水解酶基因敲除小鼠的NG2内化变性和蛋白水解酶水平测定 和细胞。在目标2中，我们将通过连接软骨将NG2的功能定义为氧化应激的介体 野生型和NG2基因敲除小鼠的变性与氧化应激、内质网应激和自噬的标志 和细胞。这些目标共同定义和评估了一种全新的软骨细胞分子机制。 与已知引起TMD的机械和代谢氧化应激相关的功能。长 术语，我们寻求使用这些数据来解决与定义TMD的精确方法相关的临床问题 分类、预防和治疗。