In rheumatoid arthritis, proliferating synovium, containing a mixture of synovial cells, monocytes and immunocytes, developes into an invasive front. As it invades and proliferates-almost like a tumor- articular cartilage, sub-chondral bone and tendons are destroyed. Collagenase and prostaglandin E2 (PGE2) are prime mediators of the joint destruction. A model system, developed in tissue culture, uses monolayers of rabbit synovial fibroblasts treated with the tumor promoter phorbol myristate acetate (PMA). PMA2 induces these quiescent cells to proliferate and to synthesize and secrete large quantities of collagenase and PGE2. Retinoids have been shown to inhibit collagenase and PGE production by both rheumatoid and PMA-treated cells. Using the proliferative ability and the synthesis of collagenase and PGE2 by PMA-treated synovial fibroblasts as biologic markers, we will study the mechanism of action of retinoids. We will test the hypothesis that retinoids, like corticosteroids, act to inhibit collagenase production at some level of transcription. We will look for retinoid acid binding proteins in these cells and for their translocation to the nucleus, and we will examine the translation products of mRNA from retinoid-treated cells. We will study the antagonism between PMA, transforming growth factor (TGF) and retinoids. We will measure the ability of PMA and TGF to increase cell proliferation and the ability of retinoids, alone or in combination with agents that inhibit PGE2 formation (indomethacin and corticosteroids) to inhibit this proliferation. Finally, we will study the ability of retinoids to modulate synovial cell/monocyte interactions, and thus possibly influence the behavior of these cells within rheumatoid synovium. By using this inducible model of PMA-stimulated rabbit synovial fibroblasts, we can study the action of retinoids on normal cells, derived from healthy animals. Results may be potentially important in understanding the pathophysiology of the proliferative and destructive lesion of rheumatoid arthritis (and of ways to control it) and in providing us basic information on retinoid biology.