Effects on mucopolysaccharides

In rheumatic disease, the main pathological manifestations appear in connective tissue, the chief constituents of which are collagen, elastin and mucopolysaccharides. The last, apart from hyaluronic acid and chondroitin of cornea, are all sulphate esters , the sulphate groups of which are in a dynamic state with a short biological half-life. The sulphate exchange is under enzymic control and can be decreased in vitro and in vivo by corticosteroids . Bostrom and Mansson examined the effects of a number of salicylates on the incorporation of S into calf costal cartilage slices in vitro. 

The influence of steroidal and non-steroidal antirheumatic drugs on the in vitro formation of cartilage and its constituent polysaccharides has been studied in tissue culture so that an examination of the biosynthesis rather than the turnover of any constituents of preformed cartilage could be made . Cortisone, hydrocortisone and salicylate in high concentrations inhibit chondrogenesis and S-incorporation, but cinchophen and phenylbutazone are inactive. The sulphation of chondroitin may be more dependent upon the supply of energy from respiration than is the biosynthesis of chondroitin. 

Whitehouse and Bostrom provide evidence that, in both cornea and cartilage, salicylic acid and some anti-inflammatory steroids reduce the uptake of extracellular sulphate ions by the tissues and also partially inhibit the incorporation of intracellular inorganic sulphate into the sulphated polysaccharides. 2,3-Dihydroxybenzoic acid is also effective, though to a lesser extent than salicylic acid 2,5- and 2,6-dihydroxybenzoic acids are inactive. The authors suggest that these effects may be due to a common action of the drugs on processes generating ATP within the tissues. In vivo experiments demonstrate that 100 mg/kg of sodium salicylate intraperitoneally inhibits S incorporation into polysaccharide sulphates of rat-rib cartilage. 

Whitehouse , and Whitehouse and Bostrom investigated the incorporation of glucose- G, acetate- G and S04 into mucopolysaccharide sulphates, and the oxidation of glucose- G, acetate-pyruvate- C and octanoate- C in cartilage and cornea. The incorporation of the above substances is inhibited by salicylate, phenylbutazone and cinchophen, all of which have an immediate effect on the reaction, and by hydrocortisone and chloroquine which are effective only after a time lag of 1-2 hours. There seems to be some relationship between the inhibition of uptake by non-steroidal compounds and their anti-inflammatory activities. It is concluded that the drugs diminish anabolic reactions in connective tissue by inhibiting fundamental exergonic reactions. 

The action of drugs on mucopolysaccharide synthesis cannot explain their action in acute inflammation, but it is conceivable that those drugs which affect chronic inflammation may do so by this means. 

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