The Impact of COL6A3 Mutation on Inflammatory Susceptibility in Osteoarthritis

COL6A3 突变对骨关节炎炎症易感性的影响

• 批准号: 10612768
• 负责人: Zainab Harissa
• 金额: $ 4.77万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612768
• 关键词: 3-Dimensional; Affect; Area; Atomic Force Microscopy; Biochemical; Biological; Biomechanics; COL6A3; Cartilage; Cartilage Matrix; Catabolism; Cell Culture Techniques; Chemicals; Chondrocytes; Collagen Type VI; Cytoskeleton; DNA Sequence Alteration; Degenerative polyarthritis; Disease; Disease Progression; Disease model; Elasticity; Environment; Environmental Risk Factor; Equilibrium; Exposure to; Extracellular Matrix; Fluorescence Recovery After Photobleaching; Gene Expression; Genes; Genetic; Homeostasis; Human; IL6 gene; In Situ; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-1; Ion Channel; Knock-out; Link; Measures; Mechanics; Mediating; Mediator; Metabolic; Modeling; Modulus; Molecular; Molecular Biology; Mutate; Mutation; Onset of illness; Pain; Pathogenesis; Pathway interactions; Perception; Persons; Physiological; Predisposition; Production; Property; Proteins; Research; Risk; Risk Factors; Role; Signal Transduction; Testing; Therapeutic Uses; Tissues; Training; United States; Weight-Bearing state; Work; antagonist; arthropathies; cartilage degradation; cell type; cytokine; disability; disorder prevention; disorder risk; early onset; environmental stressor; exome sequencing; exposed human population; human model; induced pluripotent stem cell; inflammatory marker; joint inflammation; mechanical drive; mechanical load; mechanical properties; mechanical signal; mechanical stimulus; mechanotransduction; novel; response; symptom management; targeted treatment; therapeutic development; transmission process

PROJECT SUMMARY Osteoarthritis (OA) is a painful and debilitating joint disease affecting over 30 million people in the United States alone. OA is characterized by the progressive degeneration of cartilage matrix primarily due to an imbalance of chondrocyte catabolic and anabolic activities arising from genetic, chemical, and mechanical risk factors. Current non-surgical treatments for OA rely simply on managing symptoms primarily owing to a lack of a full understanding of the molecular mechanisms leading to disease onset and pathogenesis. In recent exome sequencing studies, genetic mutation in collagen type VI alpha three (COL6A3) has been identified to increase risk of developing early-onset OA. COL6A3 encodes for one of the proteins that forms collagen type VI (COL6), a critical component of the chondrocyte’s pericellular matrix (PCM). COL6 is a key mediator of the chondrocyte’s transduction of chemical and mechanical cues by maintaining the structural integrity of the PCM. It is likely that mutation in COL6A3 may exacerbate OA by altering PCM properties; however, the mechanisms leading to disease remain unknown. In this proposal, we will determine the molecular link between COL6A3 mutation and OA etiopathogenesis. We hypothesize that COL6A3 mutation increases the effect of inflammation on chondrocyte catabolism and PCM degradation, leading to alterations in the normal chondrocyte metabolic response to mechanical loading thereby initiating a cycle of cartilage degeneration. To complete the proposed studies, we have developed a novel in vitro “OA-in-a-dish” disease model using human induced pluripotent stem cell (hiPSC)-derived chondrocytes gene-edited to introduce the COL6A3 mutation. In specific aim 1, we will assess the effects of proinflammatory cytokines on the biological and mechanical properties of hiPSC-derived cartilage with and without the COL6A3 mutation. Then, in specific aim 2, we will determine the effect of this mutation on chondrocyte mechanotransduction following proinflammatory cytokine treatment. This proposal aims to determine a mechanistic cause for increased predisposition to early on-set OA due to mutation in COL6A3, that can be used for the identification of targets for therapeutic development. Completion of these studies will better define the mechanisms that mechanical, genetic, and biochemical factors act in concert and lead to OA.

PROJECT SUMMARY Osteoarthritis (OA) is a painful and debilitating joint disease affecting over 30 million people in the United States alone. OA is characterized by the progressive degeneration of cartilage matrix primarily due to an imbalance of chondrocyte catabolic and anabolic activities arising from genetic, chemical, and mechanical risk factors. Current non-surgical treatments for OA rely simply on managing symptoms primarily owing to a lack of a full understanding of the molecular mechanisms leading to disease onset and pathogenesis. In recent exome sequencing studies, genetic mutation in collagen type VI alpha three (COL6A3) has been identified to increase risk of developing early-onset OA. COL6A3 encodes for one of the proteins that forms collagen type VI (COL6), a critical component of the chondrocyte’s pericellular matrix (PCM). COL6 is a key mediator of the chondrocyte’s transduction of chemical and mechanical cues by maintaining the structural integrity of the PCM. It is likely that mutation in COL6A3 may exacerbate OA by altering PCM properties; however, the mechanisms leading to disease remain unknown. In this proposal, we will determine the molecular link between COL6A3 mutation and OA etiopathogenesis. We hypothesize that COL6A3 mutation increases the effect of inflammation on chondrocyte catabolism and PCM degradation, leading to alterations in the normal chondrocyte metabolic response to mechanical loading thereby initiating a cycle of cartilage degeneration. To complete the proposed studies, we have developed a novel in vitro “OA-in-a-dish” disease model using human induced pluripotent stem cell (hiPSC)-derived chondrocytes gene-edited to introduce the COL6A3 mutation. In specific aim 1, we will assess the effects of proinflammatory cytokines on the biological and mechanical properties of hiPSC-derived cartilage with and without the COL6A3 mutation. Then, in specific aim 2, we will determine the effect of this mutation on chondrocyte mechanotransduction following proinflammatory cytokine treatment. This proposal aims to determine a mechanistic cause for increased predisposition to early on-set OA due to mutation in COL6A3, that can be used for the identification of targets for therapeutic development. Completion of these studies will better define the mechanisms that mechanical, genetic, and biochemical factors act in concert and lead to OA.