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: 10596064
• 负责人: David Andrew Reed
• 金额: $ 41.18万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596064
• 关键词: Acceleration; Address; Affect; Apoptosis; Arthritis; Attenuated; Autophagocytosis; Binding; Biochemical; Bioreactors; CSPG4 gene; Cartilage; Cartilage Diseases; Cell Death; Cells; Chondrocytes; Clinical; Collagen Type VI; Communication; Cytoprotection; Data; Degenerative polyarthritis; Disease; Early Intervention; Endocytosis; Exposure to; Extracellular Matrix; FRAP1 gene; Fibroblasts; Flow Cytometry; Functional disorder; Goals; Health; Hip region structure; Histology; Human; Immunohistochemistry; Impairment; In Vitro; Inflammatory; Injury; Integrin Binding; Joints; Knockout Mice; Knowledge; Limb structure; Link; Maintenance; Mandible; Mechanical Stress; Mechanics; Mediating; Membrane; Modeling; Molecular; Monoclonal Antibodies; 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; Sirolimus; Stress; Temporomandibular Joint; Temporomandibular Joint Disorders; Temporomandibular Joint Dysfunction Syndrome; Temporomandibular joint arthritis; Temporomandibular joint osteoarthritis; Testing; Western Blotting; Work; arthropathies; cartilage degradation; cost; design; experimental study; immunocytochemistry; in vivo; inhibitor; innovation; joint injury; joint mobilization; mouse model; neuron loss; novel; novel therapeutic intervention; pre-clinical; receptor; response; response to injury; 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 through activation of the mTORC1 pathway. 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 with the potential to attenuate the progression of TMJ OA and restore TMJ health in patients that would otherwise require alloplastic total joint replacement.

抽象的 TMJ OA中纤维软骨细胞的细胞 - 矩阵调节 颞下颌关节（TMJ）的疾病影响3-7％的人群和骨关节炎（OA） 是与TMJ功能障碍相关的最常见病理。 TMJ OA是一种软骨疾病 变性和软骨细胞凋亡。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。自噬是对 TMJ OA已被证明是衰减软骨进展的可行治疗靶点 退化。知识的主要差距是机械和炎症应力如何导致最终 自噬，凋亡和软骨变性的抑制。为了解决这个差距，我的实验室已经发展 TMJ OA的临床前手术诱导小鼠模型的专业知识与人类紧密相对应 条件并确定了三步的发病机理模型，将机械损伤与ECM变化联系起来，并且 软骨细胞凋亡包括1）手术诱导的TMJ后胶原蛋白VI（COL VI）的耗竭 OA 2）Col VI软骨细胞受体，神经/神经胶质抗原2（NG2）的蛋白水解和3）还原 自噬。我们研究的总体目标是检验损伤引起的COL VI变性的假设 激活NG2依赖性途径，该途径通过抑制自噬来加速TMJ软骨变性。 根据本应用程序中包含的初步数据，我们设计了一个研究计划 机械机械地定义了NG2与Col VI的结合对于维持自噬的必要 MTORC1途径的激活。提出的工作具有创新性，因为它专注于一种新的分子 软骨细胞功能的机制，将基质功能障碍与损失的细胞保护作用联系起来 细胞机制与TMJ OA的进展有关。这项研究的意义在于 在TMJ OA的临床问题上的潜在应用，代表了我们对TMJ的了解 OA病理生理学。我们预计我们的研究结果将为新的治疗方法提供信息 减轻TMJ OA进展并恢复患者TMJ健康的潜力 需要同种塑料总关节置换。