In vitro studies on synovial membrane; effect of some therapeutic agents and chemically related compounds.

Considerable knowledge has been gained from the clinical study of various therapeutic agents in rheumatoid arthritis, yet comparatively little information is available on the metabolic action of these substances at the tissue level. A satisfactory in vitro approach to this problem could not be made until it could be established that in vitro metabolic changes occurred in the presence of rheumatoid disease in the synovium. We have shown that normal synovial membrane was a tissue with an extremely low oxidative metabolism, though its glycolysis was readily measurable. The tissue reaction to the disease involved the appearance of considerable oxidative metabolism, as well as an increase in glycolysis (Dingle and Page Thomas, 1956). It was also noted that the highest rate of metabolism was found in villous tissues, and that a positive correlation existed between the proliferative state of the disease in the knee joint and the metabolism of the excised tissue. In the cell, the synthesis of energy-rich bonds is achieved mainly by the oxidative breakdown of carbohydrate. The increase in synovial oxidative metabolism in rheumatoid disease is probably associated with the increased energy requirements of the proliferating synovium. Hence, any agent which alters this metabolic state might play a part in modifying the response of the tissue to the disease stimulus. Preliminary results have indicated that hydrocortisone is a potent inhibitor of synovial metabolism (Page Thomas and Dingle, 1955). The degree of inhibition of oxygen uptake produced in vitro by a standard concentration of hydrocortisone on rheumatoid synovia of varying degrees of metabolic activity was greatest in those tissues which exhibited the highest oxygen uptake (Page Thomas and Dingle, 1957). In this series of experiments, the in vitro action of hydrocortisone has been compared with Compound B (corticosterone), Compound S (11 -desoxy 17-hydroxycorticosterone), cortisone (1 -dehydro 17-hydroxycorticosterone), and DOCA (desoxycorticosterone acetate). Other compounds which have been investigated are o-hydroxy benzoic acid (salicylic acid), mand p-hydroxybenzoic acids, phenylbutazone (Butazolidin), and insulin. Materials