AGE RELATED DIFFERENCES IN CHONDROCYTE MMP-8

软骨细胞 MMP-8 的年龄相关差异

• 批准号: 2631405
• 负责人: SUSAN CHUBINSKAYA
• 金额: $ 6.44万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2631405
• 关键词: age difference; aging; animal old age; ankle; cartilage; chondrocytes; chondroitin sulfates; collagenase; enzyme activity; gene expression; human tissue; immunocytochemistry; in situ hybridization; interleukin 1; juvenile animal; messenger RNA; oligonucleotides; polymerase chain reaction; protein degradation; proteoglycan; tissue /cell culture; western blottings

Osteoarthritis (OA) is a debilitating joint disease affect primarily the elderly. The prevalence of symptomatic OA is higher in the knee joint, than in the ankle. As progressive cartilage degeneration seen in OA increased markedly during adult life, it is important to learn more about the mechanisms driving normal aging. An advantage of the proposed study using the ankle cartilage from human organ donor is the opportunity of documenting cartilage changes in a joint that rarely develops OA. Thin ankle cartilage could serve as an ideal model for studying normal aging processes which do not have impact of changes leading to disease. A significant finding of this study to data has been the establishment of a grading system for joints which cartilage has been taken so that the cartilages could be identified as normal or damaged distinguishing between normal (non pathologically progressive) aging process and pathologically progressive degeneration of cartilage. By eliminating from our studies cartilages with signs of OA, we intend to identify only those biochemical and/or molecular biological differences which are age-related. The uniqueness of this project is that we have unlimited access to human tissue. All ankle cartilages to be tested are from human organ donors collected through the Regional Organ Bank of Illinois within 24 hours of death. For the proposed studies we have chosen to investigate the role of one of the matrix metalloproteinase (MMP), MMP-8, in aging of human ankle cartilage from four age groups: 1) under 10 years old; 2) 20-40 years old; 3) 40-60 years old and 4) 60 and over years old. We have selected this proteinase because of its catalytic activity against both collagen and aggrecan, the major components of the extracellular matrix. Our preliminary data indicate that in relatively young adult ankle articular cartilage the expression of MMP-8 mRNA is negative or barely detectable, however this proteinase is highly up-regulated in OA cartilages from elderly patients. We hypothesize that with normal aging of ankle cartilage some modulation of MMP-8 expression and activity is taking place, but does not lead to accelerated catabolism of aggrecan and collagen. The overall goals of the proposed studies are 1) to define age-related changes in chondrocyte MMP-8 and 2) to study specific changes which the proteinase undergoes with age if cartilage degeneration is enhanced by exposure to catabolic mediator, interleukin-1, at concentrations effective in altering matrix steady state metabolism. Once the involvement of MMP-8 in normal aging of cartilage is better understood, the approaches presented here could prove most helpful in defining the role of MMP-8 in disease-related processes (long-term goal).

骨关节炎（OA）是一种使人衰弱的关节疾病，主要影响 老人膝关节中症状性OA的患病率较高， 而不是脚踝由于在OA中观察到进行性软骨退变， 在成年期明显增加，重要的是要了解更多关于 驱动正常衰老的机制拟议研究的一个优点是 利用人体器官捐献者的踝关节软骨， 记录了很少发生OA的关节中的软骨变化。薄 踝关节软骨可以作为研究正常衰老的理想模型 没有导致疾病的变化的影响的过程。一 这项研究的一个重要发现是建立了一个 分级系统的关节软骨已采取，使 软骨可以被识别为正常或受损， 正常（非病理性进行性）衰老过程和病理性 软骨逐渐退化。从我们的研究中剔除 软骨与OA的迹象，我们打算确定只有那些生化 和/或与年龄相关的分子生物学差异。的 这个项目的独特之处在于，我们可以无限地访问人类 组织.所有要测试的踝关节软骨都来自人体器官捐赠者 在24小时内通过伊利诺伊州区域器官库收集 死亡对于拟议的研究，我们选择调查以下因素的作用： 基质金属蛋白酶（MMP）之一MMP-8在人踝关节衰老中的作用 四个年龄组的软骨：1）10岁以下，2）20-40岁， 3)40-60岁和4）60岁及以上。我们选择了这个 蛋白酶，因为它对胶原蛋白和 聚集蛋白聚糖，细胞外基质的主要成分。我们 初步数据表明，在相对年轻的成年踝关节， 软骨MMP-8 mRNA表达阴性或几乎检测不到， 然而，这种蛋白酶在OA软骨中高度上调， 老年患者。我们假设踝关节软骨的正常老化 MMP-8的表达和活性发生了一些调节，但 不会导致聚集蛋白聚糖和胶原蛋白的加速分解。整体 这些研究的目的是：（1）确定与年龄有关的变化， 软骨细胞MMP-8和2）研究蛋白酶的特异性变化， 如果软骨退化因暴露于 分解代谢介质，白细胞介素-1，在浓度有效改变 基质稳态代谢一旦MMP-8参与正常 软骨的老化是更好地理解，这里提出的方法， 可以证明最有助于确定MMP-8在疾病相关的作用， 过程（长期目标）。