Calcium- containing crystal-deposition diseases, which include calcium pyrophosphate dihydrate and basic calcium phosphate crystals, are a group of clinically heterogeneous arthritides which cause significant morbidity in the elderly. Intra-articular calcium-containing crystals produce the acute inflammatory episodes of pseudogout as well as the chronic degenerative arthritis associated with chondrocalcinosis and Milwaukee Shoulder Syndrome. The etiology of these diseases is unknown. As present understanding of the mechanisms of pathologic calcification is limited, no reliable method exists to prevent calcium crystals deposition or to effect resorption. The overall objective is to determine the pathogenesis of the degenerative arthropathies associated with the deposition of these crystals in articular tissues in order to develop a rational means of preventing or reversing the consequences of such deposition. This proposal focuses on the interaction between cells and calcium crystals. Specifically emphasized will be experiments to test: (1) to determine how crystals activate cellular responses; (2) to evaluate 2 potential therapeutic agents, phosphocitrate (PC) and prostaglandin (PG)El. Four hypotheses to be tested are: (1) crystals induce macrophages to synthesize and release cytokines e.g. tumor necrosis factor-a which can reinforce the action of crystals on synoviocytes and/or induce chondrocytes to secrete enzymes leading to the cartilage degeneration (paracrine pathway); (2) cell activation by crystals is due to the physical interaction of crystal surface and cell membrane; (3) crystal-induced metalloproteinase synthesis can be dissociated from mitogenesis and is the result of early cellular responses e.g. protein kinase C activation; (4) PC and PGEl are potential therapeutic agents based on knowledge of the biologic effects of calcium-containing crystals. Their effects on the early crystal-induced cellular responses will be examined. A new form of sustained release microcarriers as a delivery system for PC will be tested. Fibroblast, chondrocyte, and macrophage cultures and a Murine Progressive Ankylosis animal model will be used for the studies.
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