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。 我们建议确定调节代谢的异常是如何 骨关节炎关节软骨的通路参与病因 和发病机制。 实验设计基于 假设白细胞介素-1（IL 1）和其他细胞因子参与了 软骨重塑，当产生过量时，可能导致随后的 骨关节炎的关节破坏。 以前的工作，这项赠款已导致隔离， 软骨降解酶的表征，目前称为软骨降解酶。 基质溶素或基质金属蛋白酶3（MMP-3），主要的软骨 降解IL-1诱导的蛋白酶。 将进行研究以确定 这种酶以潜在的非活性形式分泌， 我们将寻求控制其激活的因素。 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，我们最近获得了一个cDNA， 基质分解素mRNA。 DNA探针将用于研究 基质分解素生物合成的调节机制，并检测和 定量其在正常和患病软骨组织中的mRNA。 我们进一步建议测量正常和非正常关节滑液中的IL-1， 骨关节炎患者;并使用DNA探针，测量信使RNA编码 IL-1在正常和骨关节炎软骨细胞中的表达。 这种感受器 对正常和OA软骨细胞上的细胞因子进行定量。 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.