SPECIFIC-INHIBITION OF BASIC CALCIUM-PHOSPHATE AND CALCIUM PYROPHOSPHATE CRYSTAL-INDUCTION OF METALLOPROTEINASE SYNTHESIS BY PHOSPHOCITRATE

Calcium pyrophosphate dihydrate (CPPD) and basic calcium phosphate (BC P) crystal deposition diseases are a group of heterogeneous arthritide s which are a significant source of morbidity in the elderly. Both cry stals induced mitogenesis and metalloproteinase (MP) synthesis and sec retion by fibroblasts and chondrocytes which may promote degradation o f intra-articular tissue. We have previously shown that phosphocitrate (PC), an inhibitor of hydroxyapatite crystallization, specifically bl ocks BCP crystal-induced mitogenesis in 3T3 cells. This led us to exam ine the effect of PC on BCP and CPPD crystal induction of MP synthesis in human fibroblasts. PC (10(-3) to 10(-4) M) specifically inhibited the crystal-induced collagenase and stromelysin mRNA accumulation whil e having no effect on epidermal growth factor-induced or basal levels of mRNA for both enzymes. Western blots (collagenase) of conditioned m edia confirmed that PC blocked crystal-induced proteinase secretion as well. Moreover, PC (10(-3) M) also blocked the crystal induction of c -fos and c-jun. Since FOS and JUN proteins form a transacting activato r (AP-1) for expression of collagenase and stromelysin genes, PC may b lock the synthesis of both enzymes by inhibiting the transcription of c-fos and c-jun.