CARTILAGE MATRIX PROTECTION BY FORMS OF TIMP

THE GOAL OF THIS RESEARCH IS TO EVALUATE THE ROLE OF METALLOPROTEASE INHIBITORS IN CONTROLLING THE PATHOLOGICAL PROGRESSION OF JOINT DISEASES. IN PHASE I, IT IS PLANNED TOCHARACTERIZE THE ABILITY OF FORMS OF TISSUE INHIBITORS OF METALLOPROTEINASE TO RETARD THE BREAKDOWN OF ARTICULAR CARTILAGE MATRIX IN ORGAN CULTURE MODELS OF OSTEOARTHRITIS. DURING NORMAL PHYSIOLOGY, THE SYNTHESIS, ASSEMBLY, AND DEGRADATION OF THE MATRIX ARE WELL-COORDINATED EVENTS. HOWEVER, IN CERTAIN PATHOLOGICAL CONDITIONS, SUCH AS OSTEOARTHRITIS, THE CATABOLIC PATHWAYS PREDOMINATE. ONE WAYTHAT TISSUES NORMALLY CONTROL EXTRACELLULAR MATRIX BREAKDOWN IS BY THE SECRETION OF SELECTIVE PROTEASE INHIBITORS CALLED TIMP'S. SEVERAL TYPES OF TIMP WILL BE ASSAYED FOR ENHANCED MATRIX PROTECTION. THE INHIBITORY PROPERTIES OF THESE TIMP FORMS WILL BE COMPARED USING TWO DIFFERENT PROTEASES THAT ARE PRESENT IN ARTICULAR CARTILAGE. THE MATRIX PROTECTIVE ACTION OF THE TIMP'S WILL BE DETERMINED IN STUDIES USING IL-1-INDUCED BOVINE CARTILAGE ORGAN CULTURE AND NATURALLY OCCURRING HUMAN OSTEOARTHRITIC CARTILAGE ORGAN CULTURE. EVIDENCE OF ENHANCED MATRIX PROTECTION WOULD FORM THE BASIS OF PHASE II IN VIVO STUDIES USING ANIMAL MODELS OF OSTEOARTHRITIS.