Sodium salicylate has been shown to suppress glycosaminoglycan (GAG) synthesis by articular hyaline cartilage in vitro. We investigated the in vivo effect of sodium salicylate on murine patellar cartilage, using incorporation of intraperitoneally administered 35S-sulfate as a measure of sulfated GAG synthesis. Our results indicated that a single dose of sodium salicylate (200 mg/ kg) inhibited in vivo sulfated GAG synthesis by 56%, compared with controls, and had no effect on sulfated GAG breakdown. A striking finding was that sodium sulfate treatment reduced the serum concentration of inorganic sulfate from 1.1 mM to approximately 0.3 mM, and that this serum reduction was associated with a twofold increase in urinary excretion of sulfate. Using anatomically intact patellar cartilage, in vitro studies clearly showed that, in concentrations reached in vivo (21 mM), salicylate suppressed murine chondrocyte GAG synthesis. However, in the presence of serum, the effects of 1 mM salicylate were abolished. We also found that sulfated GAG synthesis was clearly inhibited at low concentrations of sulfate (<0.5 mM). Our data indicate that sodium salicylate can suppress articular chondrocyte sulfated GAG synthesis in vivo, and that this effect may particularly be due to a drug-induced reduction of endogenous sulfate. Several nonsteroidal antiinflammatory drugs (NSAIDs) commonly used in the treatment of arthritis have been shown to provoke suppression of glycosaminoglycan (GAG) synthesis in organ cultures of normal articular cartilage (1-3). Studies have clearly shown that salicylate administration suppresses in vitro GAG synthesis in normal human articular cartilage and that degenerated cartilage is affected even more by this drug (43). In experiments on canine osteoarthritic cartilage (6), an almost complete suppression was observed at salicylate concentrations of 10-3M (14 mg%), a level which is readily achieved in human serum.
~~Because patients with rheumatic diseases often receive long-term treatment with NSAIDs, it is relevant to know whether the suppressive effect of these drugs, as observed in vitro, also occurs in vivo. A deleterious effect of salicylates on articular cartilage after long-term treatment has been shown in studies of animals (7,8). However, the chondrocyte synthetic function of salicylate-treated animals has only been tested ex vivo (7,9), and a direct action of salicylates on in vivo articular GAG synthesis has not been established.Originally, the present study was aimed at investigations of the short-term effect of sodium salicylate on in vivo sulfated GAG synthesis in normal articular cartilage. A preliminary experiment showed that sodium salicylate indeed inhibited 35S-sulfate incorporation in articular cartilage, but the most striking observation was a decrease in the serum content of 35S-sulfate, which paralleled a decrease in the endogenous serum sulfate level (10). With these observations and those of others (ll), who found that the lowering of environmental inorganic sulfate per se may
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