METABOLISM IN NORMAL AND OSTEOARTHRITIC CARTILAGE

这项建议的目的是为了更好地了解 调节软骨基质降解和重塑的过程。 我们建议确定调节性代谢异常是如何 骨性关节炎关节软骨的致病机制 以及该病的发病机制。实验设计是基于 白介素1(IL1)和其他细胞因子参与的假说 软骨重塑和当过度生产时可能会导致随后的 骨性关节炎的关节破坏。 之前在这笔赠款上的工作导致了隔离和 软骨降解酶的特性，目前被称为 基质分解素或基质金属蛋白酶3(MMP3)，主要软骨 IL-1诱导的降解酶。将进行研究以确定 这种以潜在的非活性形式分泌的酶是如何被激活的 内源性；我们将寻找控制其激活的因素。 已经获得的蛋白质序列数据将用于合成 寡核苷酸探针。此外，我们最近还获得了一个cDNAto 基质分解素基因。DNA探针将用于研究 基质分解素生物合成的调控机制及其检测和 定量检测其在正常和病变软骨组织中的表达。 我们进一步提出了检测正常人和正常人滑液中IL-1的方法。 骨关节炎患者；并使用.DNA探针测量信使RNA编码 IL-1在正常软骨细胞和骨关节炎软骨细胞中的表达。它的受体 对正常软骨细胞和骨关节炎软骨细胞上的细胞因子进行定量。 对这些软骨代谢途径的进一步定义是主要的 对我们理解骨关节炎的重要性。

The objective of this proposal is to obtain a better understanding of those processes regulating the degradation and remodeling of cartilage matrix. We propose to determine how abnormalities in the regulatory metabolic pathways of osteoarthritic articular cartilage are involved in the etiology and pathogenesis of the disease. The experimental design is based on the hypothesis that interleukin-1 (IL1) and other cytokines are involved in cartilage remodeling and when produced in excess may lead to the subsequent joint destruction of osteoarthritis. Previous work on this grant has resulted in the isolation and characterization of a cartilage degrading enzyme, presently referred to as stromelysin or matrix metalloprotease 3 (MMP-3), the major cartilage degrading protease induced by IL-1. Studies will be performed to determine how this enzyme, secreted in a latent inactive form, is activated endogenously; and we will seek the factors which control its activation. Protein sequence data already obtained will be used for synthesis of oligonucleotide probes. In addition we have recently obtained a cDNA to the stromelysin mRNA. The DNA probes will be used in studying the regulatory mechanisms of stromelysin biosynthesis and to detect and quantitate its mRNA in normal and diseased cartilage tissue. We further propose to measure IL-1 in synovial fluid of normal and osteoarthritic patients; and using.DNA probes, measure messenger RNA coding for IL-1 in normal and osteoarthritic chondrocytes. The receptors for this cytokine on normal and OA chondrocytes will be quantitated. Further definition of these cartilage metabolic pathways are of primary importance in our understanding of osteoarthritis.