EFFECTS OF THAPSIGARGIN, AN INTRACELLULAR CALCIUM-MOBILIZING AGENT, ON SYNTHESIS AND SECRETION OF CARTILAGE COLLAGEN AND PROTEOGLYCAN

The calcium-mobilizing agents thapsigargin and 2,5-di-(tert-butyl)-1,4 -benzohydroquinone were shown to markedly elevate the intracellular ca lcium concentration of chick embryo chondrocytes in a dose-dependent m anner. Under these conditions, the metabolism of macromolecules was va riably affected. The synthesis and secretion of protein in general, an d of collagen in particular, were significantly inhibited; in contrast , proteoglycan synthesis (but not glycosaminoglycan synthesis) was inh ibited, whereas secretion was unaffected. Flunarizine. which prevented the thapsigargin-induced intracellular calcium elevation, and EGTA, w hich caused only a transient thapsigargin-induced intracellular calciu m elevation, did not revel-se these alterations. It was concluded, the refore, that the observed effects of thapsigargin and 2,5-di-(tert-but yl)-1,4-benzohydroquinone chondrocyte macromolecule metabolism were no t related to the ability of these drugs to increase the cytosolic free calcium concentration but may have been due to the specific depletion of the calcium sequestered in the endoplasmic reticulum. The differen tial effect of these drugs on protein and proteoglycan secretion sugge sts that the intracellular trafficking of these two classes of macromo lecules may be controlled independently.