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基质调节 颞下颌关节 (TMJ) 疾病影响 3-7% 的人口和骨关节炎 (OA) 是与颞下颌关节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。自噬是最早的细胞反应之一 TMJ OA 已被证明是减缓软骨进展的可行治疗靶点 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的 抑制自噬、细胞凋亡和软骨变性。为了解决这一差距，我的实验室开发了 拥有与人类密切相关的 TMJ OA 临床前手术诱导小鼠模型的专业知识 条件并确定了将机械损伤与 ECM 变化联系起来的三步发病机制模型， 软骨细胞凋亡，包括 1) 手术诱导 TMJ 后 VI 型胶原蛋白 (Col VI) 的消耗 OA 2) Col VI 软骨细胞受体、神经元/神经胶质抗原 2 (NG2) 的蛋白水解和 3) 减少 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，通过抑制自噬加速 TMJ 软骨退化。 根据本申请中包含的初步数据，我们设计了一项研究计划 从机制上定义 NG2 与 Col VI 的结合对于维持自噬是必需的 mTORC1 通路的激活。拟议的工作具有创新性，因为它专注于一种新型分子 软骨细胞功能机制，将基质功能障碍与细胞保护作用的丧失联系起来 TMJ OA 进展中涉及的细胞机制。这项研究的意义在于 TMJ OA 临床问题的潜在应用，代表了我们对 TMJ 知识的飞跃 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 有可能减缓 TMJ OA 的进展并恢复患者的 TMJ 健康 需要异体全关节置换术。