MODULATION OF PHENOTYPIC-EXPRESSION OF FIBROBLASTS BY ALTERATION OF THE CYTOSKELETON

Several studies indicate that the cytoskeleton may be involved in modulating the cellular response to environmental signals. We have studied the role of the cytoskeleton in regulating glycosaminoglycan (GAG) synthesis and secretion, hyaluronate (HA) endocytosis, the activities of hexoglycosidases, protein synthesis and secretion. Fibroblasts were treated with colchicine (1-8 mu M) and nocodazole (1 or 4 mu M) to alter microtubules or cytochalasin B (0.5-4 mu M) to alter microfilaments. Colchicine inhibited GAG synthesis and secretion in a concentration-dependent manner. It reduced protein and sulphated GAG secretion, while HA secretion was not affected. Concentration-dependent disruption of microtubules from the periphery toward the cellular centre with nocodazole inhibited only the secretion of GAG. Centrosomal microtubles appeared to be required to promote GAG synthesis; intact microtubules promoted the transport of secretory products, intercompatmental transport of lysosomal enzymes and lysosome maturation, but not protein synthesis and HA secretion. Cytochalasin B treatment inhibited, in a concentration-dependent manner, the synthesis and secretion of GAGs and proteins, and the endocytosis of HA. Intact microfilament meshworks appeared to be required to promote synthesis and secretion of proteins and proteoglycans and to contribute to the transmembrane control of receptor-mediated endocytosis. Drug treatment of concanavalin A (Con A)-stimulated fibroblasts inhibited the stimulation of GAG synthesis. It is probable that this effect may result, in part, from drug-induced effects on Con A-mediated endocytosis.