IL1 BETA AND MECHANICAL FORCES EFFECTS ON CARTILAGE

IL1 Beta 和机械力对软骨的影响

• 批准号: 2080941
• 负责人: MARTHA L GRAY
• 金额: $ 10.95万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-07-10 至 1997-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2080941
• 关键词: cartilage disorder; cartilage metabolism; cytokine; dosage; extracellular matrix; interleukin 1; mechanical stress; mucopolysaccharides; osteoarthritis; rheumatoid arthritis; tissue /cell culture

Degenerative and inflammatory disorders of cartilage such as osteoarthritis and rheumatoid arthritis are debilitating diseases which affect large numbers of people. Cartilage functions as a mechanical bearing material, and the mechanical integrity of the tissue is a reflection of the architecture and composition of cartilage matrix macromolecules. Human interleukin-1beta (IL-1beta) promotes cartilage destruction and bone resorption, and reduces the rate at which matrix glycosaminoglycans (GAGs) are synthesized. In culture, mechanical forces have been shown to enhance or diminish the rate of GAG synthesis, depending on the magnitude and frequency of loading. The goals of this project are to determine the coupled effects of compressive mechanical loading and IL-1beta on the mechanical properties (dynamic and static stiffness) and biochemical properties (GAG loss and synthesis) of cartilage in explant culture. It will be determined if mechanical loads can exacerbate or ameliorate the loss of tissue GAG seen with IL-1beta alone. Moreover, the utility of the naturally occurring IL-1 receptor antagonist (IL-1ra) in blocking the effects of IL-1beta will be evaluated in the presence of applied mechanical loading. In addition, a mutant protein (IL-1betaR-G) which in non- cartilage systems exhibits a partial defect in signal transduction (including minimal stimulation of prostromelysin and procollagenase mRNA) will be evaluated to determine its effects on cartilage. GAG synthesis and loss and tissue mechanical properties will be measured while cartilage is cultured in one of four conditions: (1) no dynamic mechanical loading and no IL-1; (2) no loading with IL-1; (3) loading but no IL-1; and (4) loading with IL-1. To evaluate the physical processes involved in eliciting the cartilage response, two mechanical loading regimens are proposed: one in which a large deformation is slowly applied, leading to substantial volume change during each cycle; the other in which a small deformation is rapidly applied, leading to little volume change, but high hydrostatic pressures during each cycle. Finally, the effectiveness of IL-1ra in blocking IL-1 effects and of IL-1R-G in inducing IL-1-like effects will be evaluated to better understand the mechanisms involved in IL-1-mediated and force- mediated changes in cartilage metabolism. The approach used in this work has not been previously reported. As the joints of arthritic patients are both loaded and potentially exposed to IL-1 or other cytokines, this work will provide significant and information which is critical for our understanding of the progression of arthritic diseases.

软骨退行性和炎症性疾病，例如骨关节炎 和类风湿性关节炎是使人衰弱的疾病，影响很大 人数。 软骨作为机械轴承材料， 组织的机械完整性反映了 软骨基质大分子的结构和组成。 人类 白细胞介素-1β (IL-1beta) 促进软骨破坏和骨 吸收，并降低基质糖胺聚糖 (GAG) 的速率 被合成。 在文化中，机械力已被证明可以增强 或降低 GAG 合成速率，具体取决于强度和 加载频率。 该项目的目标是确定 压缩机械载荷和 IL-1beta 对 机械性能（动刚度和静刚度）和生化性能 外植体培养中软骨的特性（GAG 损失和合成）。 它 将确定机械负载是否会加剧或改善 单独使用 IL-1β 时观察到组织 GAG 损失。 此外，实用性 天然存在的 IL-1 受体拮抗剂（IL-1ra）可阻断 IL-1beta 的效果将在施加机械作用的情况下进行评估 加载中。 此外，一种突变蛋白（IL-1betaR-G）在非 软骨系统在信号转导方面表现出部分缺陷 （包括对溶原素和原胶原酶 mRNA 的最小刺激） 将进行评估以确定其对软骨的影响。 GAG合成和 软骨损失和组织机械性能将被测量 在以下四种条件之一中培养：（1）无动态机械负载并且 无IL-1； (2)不加载IL-1； (3)加载但不加载IL-1； (4)加载 与IL-1。 评估引发的物理过程 软骨反应，提出了两种机械加载方案：一种是 缓慢施加大变形，导致体积很大 每个周期都有变化；另一种是小变形迅速发生 应用，导致体积变化很小，但静水压力高 在每个周期期间。 最后，IL-1ra阻断IL-1的有效性 将评估IL-1R-G在诱导IL-1样作用中的作用和 更好地了解 IL-1 介导和强制相关的机制 介导软骨代谢的变化。 这项工作中使用的方法 以前没有报道过。 由于关节炎患者的关节 既负载并可能暴露于 IL-1 或其他细胞因子，这项工作 将提供对我们至关重要的重要信息 了解关节炎疾病的进展。