PATHOGENESIS AND THERAPY OF EXPERIMENTAL OSTEOARTHRITIS

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Osteoarthritis (OA) is the most common form of arthritis. It occurs almost universally in the aged, and results in significant disability in over 20% of patients. Recent investigations have suggested pathophysiologic pathways capable of experimental testing. It is postulated that, following an as yet unknown primary insult, activation of proteolytic enzymes degrades extracellular matrix components including proteoglycan and collagen. Degradation is followed by chondrocyte proliferation and synthetic repair. Mechanisms of proposed import in this pathway relate to release of interleukin-l (IL-1) with eventual activation of proteolytic enzymes. Growth peptides such as insulin-like growth factor-1 (IGF-1) likely play an important role in synthetic and proliferative cellular attempts at repair. Our studies will test the hypothesis that OA is associated with release of proteolytic enzymes in response to cytokines, followed sequentially by synthetic repair responses associated with growth peptides. The overall goal will be to study temporal events in OA pathophysiology, utilizing cDNA probes and molecular hybridization techniques in the well-defined partial meniscectomy model. The availability of this model allows a more precise analysis of these interplays. Aim l will define chondrocyte steady-state messenger RNA levels for proteoglycan aggregating monomer (aggrecan), link protein, stromelysin, collagenase and interleukin-l; mRNA findings will be correlated with matrix and enzyme gene end-product responses; pathophysiologic mechanisms will be further assessed utilizing an interleukin-l receptor antagonist (IL-1 RA) and a prostaglandin-El analog. Aim 2 will study responses of growth peptides and their receptors (IGF-1 and its type I receptor; and growth hormone receptor). These investigations are proposed as an approach to further understand mechanisms of OA pathophysiology, with potential for disease modulation using specific therapeutic approaches.