Cell-Matrix Regulation of Fibrochondrocytes In TMJ OA

TMJ OA 中纤维软骨细胞的细胞基质调节

• 批准号: 10214992
• 负责人: David Andrew Reed
• 金额: $ 43.29万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214992
• 关键词: Address; Affect; Antigens; Apoptosis; Arthritis; Attenuated; Autophagocytosis; Binding; Biochemical; Bioreactors; Cartilage; Cartilage Diseases; Cell Death; Cells; Chondrocytes; Clinical; Collagen Type VI; Cytoprotection; Data; Degenerative polyarthritis; Early Intervention; Exposure to; Extracellular Matrix; FRAP1 gene; Fibroblasts; Flow Cytometry; Functional disorder; Goals; Health; Human; Immunohistochemistry; Impairment; Inflammatory; Injury; Joints; Knock-out; Knockout Mice; Knowledge; Limb structure; Link; Maintenance; Mandible; Mechanics; Mediating; Microinjections; Modeling; Molecular; Monoclonal Antibodies; Monoclonal Antibody Therapy; Neurons; Operative Surgical Procedures; Outcome; Pain; Pathogenesis; Pathology; Pathway interactions; Patients; Population; Process; Proteoglycan; Proteolysis; Quality of life; Regulation; Replacement Arthroplasty; Reporting; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Stress; TNF gene; Temporomandibular Joint; Temporomandibular Joint Disorders; Temporomandibular Joint Dysfunction Syndrome; Temporomandibular joint arthritis; Temporomandibular joint osteoarthritis; Testing; Treatment Efficacy; Western Blotting; Work; base; cartilage degradation; cost; design; in vivo; innovation; joint injury; joint mobilization; mouse model; novel; novel therapeutic intervention; pre-clinical; receptor; response; therapeutic target

ABSTRACT Cell-matrix regulation of fibrochondrocytes in TMJ OA Disorders of the temporomandibular joint (TMJ) affect between 3-7% of the population and osteoarthritis (OA) is the most common pathology associated with TMJ dysfunction. TMJ OA is a disease of cartilage degeneration and chondrocyte apoptosis. One of the key factors leading to chondrocyte apoptosis is the suppression of the cytoprotective process of autophagy. Autophagy is one of the earliest cellular responses to TMJ OA and has been shown to be a viable therapeutic target for attenuating the progression of cartilage degeneration. A major gap in knowledge is how mechanical and inflammatory stress leads to the eventual suppression of autophagy, apoptosis, and cartilage degeneration. To address this gap, my lab has developed expertise in a preclinical, surgical induction mouse model of TMJ OA that closely corresponds to the human condition and identified a three-step pathogenesis model linking mechanical damage to ECM changes and chondrocyte apoptosis that includes 1) the depletion of Collagen VI (Col VI) following surgically-induced TMJ OA 2) the proteolysis of a Col VI chondrocyte receptor, Neuron/Glial antigen 2 (NG2) and 3) the reduction of autophagy. The overall goal of our study is to test the hypothesis that injury-induced Col VI degeneration activates an NG2-dependent pathway that accelerates TMJ cartilage degeneration by suppressing autophagy. Based on the preliminary data included in this application, we have designed a research plan to mechanistically define how NG2 binding with Col VI is necessary for the maintenance of autophagy and how NG2 monoclonal antibody therapy can attenuate the progression TMJ cartilage degradation by protecting autophagy. The proposed work is innovative because it focuses on a novel molecular mechanism of chondrocyte function that contextually links matrix dysfunction with loss of a cytoprotective cellular mechanism implicated in the progression of TMJ OA. The significance of this research lies in the potential application to the clinical problems of TMJ OA and represents a leap forward in our knowledge of TMJ OA pathophysiology. We anticipate that the outcomes of our study will inform new therapeutic approaches that attenuate the progression of TMJ OA and restore TMJ health in patients that would otherwise require alloplastic total joint replacement.

摘要 TMJ骨关节炎中纤维软骨细胞的细胞基质调节 影响3-7%人群的TMJ紊乱和骨关节炎(OA) 是与TMJ功能障碍有关的最常见的病理。摘要TMJ骨关节炎是一种软骨疾病。 退变和软骨细胞凋亡。导致软骨细胞凋亡的关键因素之一是 抑制自噬的细胞保护过程。自噬是最早的细胞反应之一 已被证明是延缓软骨进展的一个可行的治疗靶点。 退化。知识上的一个主要差距是机械和炎症应激如何导致最终 抑制自噬、细胞凋亡和软骨退变。为了解决这一差距，我的实验室开发了 临床前手术诱导小鼠TMJ OA模型的专业知识，该模型与人类密切相关 并确定了一个将机械损伤与细胞外基质变化联系起来的三步发病模型 软骨细胞的凋亡，包括1)手术诱导的TMJ后VI型胶原(Col VI)的耗竭 OA2)Col VI软骨细胞受体，神经元/神经胶质抗原2(NG2)的蛋白分解和3)减少 自噬。我们这项研究的总体目标是检验这样一种假设，即损伤导致的VI型胶原退变 激活NG2依赖的途径，通过抑制自噬加速TMJ软骨退化。 根据这份申请中包含的初步数据，我们设计了一项研究计划，以 机械地定义NG2如何与Col VI结合是维持自噬所必需的以及如何 NG2单抗治疗可延缓进展性TMJ软骨降解 自噬。这项拟议的工作具有创新性，因为它专注于一种新的分子机制 软骨细胞功能将基质功能障碍与细胞保护机制的丧失联系起来 与TMJ骨关节炎的进展有关。这项研究的意义在于潜在地应用于 TMJ骨关节炎的临床问题，代表着我们对TMJ骨关节炎病理生理学知识的一次飞跃。我们 预计我们的研究结果将为新的治疗方法提供信息，以减轻 需要同种异体全关节成形术的患者TMJ骨关节炎的进展和恢复健康 替补。