Salicylate‐induced depletion of endogenous inorganic sulfate. Potential role in the suppression of sulfated glycosaminoglycan synthesis in murine articular cartilage

Abstract

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 SALI...

Fasting serum sulfate levels before and after development of osteoarthritis in participants of the veterans administration normative aging longitudinal study do not differ from levels in participants in whom osteoarthritis did not develop

“…It is noteworthy that several drugs, including aspirin and acetaminophen, are metabolized for excretion by conjugation with sulfate. Use of these agents has been shown to lower sulfate levels in humans (13,(24)(25)(26) and in other animals as well (18,(27)(28)(29). For these reasons, it remains possible that sulfate levels in some people under specific circumstances of protein consumption and/or drug ingestion could affect OA, even though results of the current study have shown no such effect.…”

An experimental model for hydrogen peroxide–induced tissue damage. Effects of a single inflammatory mediator on (peri)articular tissues

“…Chondrocyte proteoglycan synthesis was measured by a 35S04 incorporation technique described previously (5, 19,20). Briefly, murine patellae with surrounding tissue (leaving the cartilage intact) were pulsed for 2 hours with 20 pCi of 35S-sulfate/ml in RPMI 1640.…”

“…After washing, fixation, and decalcification, the patellae were punched out of the adjacent connective tissue. The 35S content of the patellae, which is exclusively associated with the cartilage glycosaminoglycans (20), was measured by liquid scintillation counting.…”

Decrease of inorganic blood sulfate following treatment with selected antirheumatic drugs: Potential consequence for articular cartilage

“…In mice, sodium salicylate decreases the level of inorganic sulfate by another process, i.e. sulfate diuresis [3], which is also the cause of the same phenomenon seen in salicylate treated rats [4,5]. A potential consequence of a reduced sulfate availability may be a suppression of biosynthesis of the highly sulfated proteoglycans, abundantly present in fetal skeletal tissue and cartilage, as was shown in mice and rats [3,6,7], leading ultimately to inferior tissue properties.…”