THE ROLE OF CYCLIC-3',5'-ADENOSINE MONOPHOSPHATE IN PROSTAGLANDIN-MEDIATED INHIBITION OF BASIC CALCIUM-PHOSPHATE CRYSTAL-INDUCED MITOGENESIS AND COLLAGENASE INDUCTION IN CULTURED HUMAN FIBROBLASTS

Synovial fluid basic calcium phosphate (BCP) crystals are associated with severe destructive arthropathies characterised by synovial proliferation and non-inflammatory degradation of intra-articular collagenous structures. BCP crystals stimulate fibroblast and chondrocyte mitogenesis, metalloprotease secretion and prostaglandin production. As a tissue protective effect of prostaglandins has been suggested, we recently studied the effect of PGE(1) on BCP crystal-induced mitogenesis and collagenase mRNA accumulation in human fibroblasts (HF). We demonstrated a dose-dependent inhibition of BCP crystal-induced mitogenesis and collagenase mRNA accumulation. The mechanism of PGE(1) inhibition of BCP crystal-induced mitogenesis and collagenase mRNA accumulation was therefore explored. PGE(1) (100 ng/ml) increased HF intracellular cAMP 40-fold over control. BCP alone caused no such change but inhibited the PGE(1)-induced increase in intracellular cAMP by at least 60%. The PGE(1)-induced increase in intracellular cAMP was also blocked by the adenyl cyclase inhibitor, 2',5'-dideoxyadenosine (ddA) (10 mu M) and ddA reversed the PGE(1)-mediated inhibition of BCP crystal-induced mitogenesis. Dibutyryl cAMP also inhibited BCP crystal-induced mitogenesis in a concentration-dependent manner. Agents which increase intracellular cAMP levels such as the adenyl cyclase activator forskolin and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) mimicked the effect of PGE(1) on HF collagenase mRNA levels. PGE(1) inhibits the biologic effects of BCP crystals through the cAMP signal transduction pathway and such inhibition may have significant therapeutic implications.