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.

软骨的退化性和炎症性疾病，例如骨关节炎 和类风湿关节炎正在使影响大型的疾病 人数。 软骨充当机械轴承材料， 组织的机械完整性是反映 软骨基质大分子的结构和组成。 人类 白介素1beta（IL-1Beta）促进软骨破坏和骨骼 吸收，并降低基质糖胺聚糖（GAGS）的速率 合成。 在培养中，机械力已被证明可以增强 或根据大小和 加载频率。 该项目的目标是确定 压缩机械载荷和IL-1Beta对耦合的效果对 机械性能（动态和静态刚度）和生化 在外植体培养中软骨的特性（吞咽损失和合成）。 它 将确定机械载荷是否会加剧或改善 单独使用IL-1Beta观察到的组织插科打n。 而且， 天然发生的IL-1受体拮抗剂（IL-1RA）在阻止 在使用机械的情况下，将评估IL-1BETA的效果 加载中。 另外，在非 - 软骨系统在信号转导中表现出部分缺陷 （包括最小的刺激前旋蛋白蛋白和易生蛋白酶mRNA） 将评估以确定其对软骨的影响。 插科打综合和 在软骨为时，将测量损失和组​​织机械性能 在四个条件之一中培养：（1）无动态机械载荷和 没有IL-1； （2）没有加载IL-1； （3）加载但没有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：一个 大变形被缓慢地施加，导致大量体积 在每个周期中变化；另一个小变形迅速的 应用，导致体积变化很小，但是高静水压力 在每个周期中。 最后，IL-1RA在阻断IL-1方面的有效性 效果和IL-1R-G在诱导IL-1样效应中的影响将评估为 更好地了解IL-1介导的和力涉及的机制 软骨代谢的介导变化。 这项工作中使用的方法 以前没有报道。 由于关节炎患者的关节是 这项工作既加载又可能暴露于IL-1或其他细胞因子 将提供重要的信息，这对我们至关重要 了解关节炎的进展。