These studies, conducted on early passage synovial cell mono-layers (derived from explant cultures of tissue obtained from patients with
rheumatoid arthritis), have established that
gold sodium thiomalate (GST) exposure results in dose-dependent changes in cell proliferation and
protein synthesis as a consequence of the cellular accumulation of
gold. The amount of
gold found in the cell layer is correlated with the degree of inhibition of [3H]
thymidine incorporation.
Gold remains in the cell layer of treated cells after they have been subcultured twice in the absence of GST. Exposure of cells to a concentration of GST of 100 muM for 4 days results in 50% inhibition of [3H]
thymidine incorporation. This antiproliferative effect is reversible at concentrations of 10 muM GST or less. Only partial recovery is observed after exposure to higher concentrations of GST which may be related to retained
gold. The amount of
collagen and noncollagen
protein synthesized per cell increases at concentrations of GST of 10 muM and below but decreases with concentrations above 10 muM. A dose-dependent decrease in
protein synthesized per flask and a decrease in the commitment to synthesize
collagen relative to total
protein synthesis follows exposure to GST in excess of 10 muM for 20 days which recovers partially after synovial cells are grown in GST-free medium for 10 days. An observed decrease in the percentage of
type III collagen synthesized by synovial cells after GST exposure was not observed in cells grown in GST-free medium for 5 days after exposure, indicating that this effect of
collagen synthesis is reversible. The reversible biochemical changes resulting from the exposure of cultured human synovial cells to GST are discussed as a mechanism of action of this
drug on the proliferative
synovitis that characterizes diseases such as
rheumatoid arthritis.