Calcium pyrophosphate dihydrate (CPPD) and basic calcium phosphate (BCP) crystals [hydroxyapatite (HA), octacalcium phosphate, tricalcium phosphate] are common in osteoarthritis knee effusions, and are often associated with low-grade synovial proliferation and inflammation. Calcium-containing crystals including HA, are known to have a number of biologic effects on culture cells such induction of mitogenesis, stimulation of Prostaglandin E2 (PGE2) production via the phospholipase A2/cyclo-oxygenase pathway, activation of phospholipase C and inositol phospholipid hydrolysis, induction of metalloproteinase synthesis and induction of proto-oncogenes (c-fos and c-myc). While endocytosis of HA particles is prerequisite of the mitogenic effect of calcium-containing crystals in fibroblasts, it is not known whether endocytosis is required for crystal-induced metalloproteinase synthesis. In the present series of experiments, we examine the effect of three different sizes (106, 46, and 17 microns mean diameters) well-characterized spherical HA particles on the induction of mitogenesis and metalloproteinase synthesis on human fibroblasts. We showed that endocytosis is required for HA particles to induce synthesis of metalloproteinases.