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.
