Augmentation of collagen arthritis by synthetic analogues of retinoic acid

We evaluated the effect of administering orally two synthetic analogues of retinoic acid, 13-cis-retinoic acid and all-trans-N-(4-hydroxyphenyl)-retinamide to age-matched female Sprague-Dawley rats immunized with native chick type II collagen in incomplete Freund's adjuvant. Ingestion of a diet containing 13-cis-retinoic acid was associated with a significant increase in the severity of collagen arthritis, but there was no effect on weight gain or hemagglutinating antibody titers and delayed-type hypersensitivity to type II collagen. In two separate trials, ingestion of 4-hydroxyphenyl retinamide also significantly enhanced the severity of arthritis. Monolayer cultures of dissociated synovial cells taken from arthritic rats, but not nonarthritic rats, released prostaglandin E2 (PGE2) and collagenase into the medium. The level of PGE2 production was significantly decreased by in vivo or in vitro exposure to 4-hydroxyphenyl retinamide, whereas the addition of 13-cis-retinoic acid to the cultures had no effect on PGE2 release by the arthritic synovial cells. Five rats fed the 13-cis-retinoic acid-containing diet for 5 mo did not develop clinical or histologic evidence of arthritis. These data demonstrate that both retinoids possess potent enhancing properties for an experimentally inducible autoimmune arthritis, that synovial cells produce PGE2 and collagenase in this model, and that production of PGE2 can be suppressed by 4-hydroxyphenyl retinamide.